Formulations and methods for treating conditions of the eye

ABSTRACT

The present disclosure relates to methods of treating chronic conditions of the eye, such as dry eye disease and blepharitis, as well as to methods for increasing secretion of meibum. This disclosure also relates to formulations suitable for treating chronic conditions of the eye such as dry eye disease and blepharitis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/117,393, filed Nov. 23, 2020, and U.S. Provisional Application No.63/254,958 filed Oct. 12, 2021, the disclosure of each of which ishereby incorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure relates generally to treating diseases or conditions ofthe eye.

BACKGROUND

Dry eye disease (DED) encompasses a number of disease states, defined bythe TFOS DEWS II (Ocul. Surf, 2017, 15(3), 269-650) as “a multifactorialdisease of the ocular surface characterized by a loss of homeostasis ofthe tear film, and accompanied by ocular symptoms, in which tear filminstability and hyperosmolarity, ocular surface inflammation and damage,and neurosensory abnormalities play etiological roles.” DED can begenerally divided into two classes: aqueous tear-deficient dry eye(ADDE) and evaporative dry eye (EDE), each of which can be dividedfurther into subclasses. One of the leading conditions associated withDED, and in particular EDE, is meibomian gland dysfunction (MGD), whichis itself an umbrella term encompassing several disorders, whereindisruption and obstruction of the meibomian gland negatively impacts thequality and quantity of meibum, a lipid-rich secretion that protects theocular surface from damage and premature evaporation of tears (Chhadva,et al., Ophthalmology, 2017, 124(11 Suppl), S20-S26). There areapproximately 20-40 meibomian glands in each eyelid and they areresponsible for producing meibum that coats the tears and preventspremature tear evaporation. When the meibomian glands are healthy,patent, and functioning properly, meibum assumes a liquid, olive-oillike consistency. Every blink applies an expression force to themeibomian glands and some clear liquid meibum is expressed from thegland orifice and fortifies the tear's outermost lipid layer. WithMGD-based EDE, the development of an imbalance in natural lipids andlipid chemistry results in a higher meibum melting temperature, whichultimately leads to meibum transitioning from a healthy, clear, liquidstate to a cloudy, semi-hardened state to an advanced, diseased,hardened state. Eventually as the disease progresses and the lipidchemistry of meibum worsens, the hardened meibum becomes unavailable andinexpressible resulting in a low quality tear lipid layer and prematuretear evaporation. In obstructive MGD, the blink results in little to noexpression of meibum due to its hardened physiochemical state andinexpressibility, a compromised lipid layer, and accelerated tearevaporation.

Globally, the prevalence of dry eye disease (DED) is estimated to bebetween 5 to 20 percent, and approximately 16 million Americans havebeen diagnosed. It is estimated that 86% of these DED sufferers haveMGD-associated EDE (Letup, et al., Cornea, 2012, 472-478). Those withDED suffer from either inadequate tear production, poor quality oftears, or both, which results in redness, stinging, burning, itching,light sensitivity, watery eyes, blurry vision, irregularities of theocular surface, and damage to corneal or conjunctival epithelium andtissues. It is believed that a majority of dry eye patients have atleast some degree of both aqueous deficiency and lipid deficiency.Treatment is largely palliative, and no broad cure for DED has beendeveloped.

Relatedly, blepharitis, which could be associated with MGD, is aninflammatory condition of the eyelids, that can cause irritation,reddening, itching, burning, edema, and crusting, among other symptoms.Blepharitis can lead to permanent alterations of the eyelid margin. Thecondition is generally into two categories based on location. Anteriorblepharitis occurs on the outer edges of the eyelids and is typicallyassociated with bacterial infection. Posterior blepharitis, which occurson the inner edges of the eyelids, can result when the meibomian glandsproduce reduced or poor quality meibum, resulting in excessiveevaporation of water from the ocular surface.

There are currently no FDA approved treatments for blepharitis, andthere are only four FDA approved drugs (Restasis®, Xiidra®, Cequa®, andEysuvis®) for treating dry eye, which all act to reduce inflammatoryaspects of the condition. In cases where bacterial infection results,topical or oral antibiotics may be administered, although these mightnot treat the underlying cause of the disease, and chronic use canresult in undesired toxicity or side effects. Available treatmentstrategies are therefore largely palliative, and focus on maintainingproper lid hygiene. Eyelid warming using warm compresses is the standardeyelid therapy to increase meibum fluidity in patients with obstructedmeibomian glands, but warm compresses are inexact and often ineffective(i.e., are too hot, are not hot enough for long enough, cool off toofast to do so effectively, do not conform to the eyelids sufficientlyenough to achieve requisite sufficiently elevated meibum meltingtemperatures), compliance is an issue, and chronic use can result inthermal injury to ocular tissue. Opening of obstructed meibomian glandsby physical expression or lid massage can improve secretion and dry eyesymptoms, but compliance remains an issue as with warm compresses, thenecessary procedures can cause damage to sensitive tissues (e.g.,undesirable corneal remodeling from rubbing the eyelids and applyingundesirable pressure on the cornea), and the therapeutic effects areshort-lived.

Accordingly, there is a need for effective, long-term methods oftreating disorders of the eye, including DED and blepharitis,particularly when the disorder is due to obstructed meibomian glands dueto hardened meibum, and when the disorder persists chronically, overmonths, years, or an entire lifetime.

SUMMARY

Formulations and methods for treating dry eye disease are disclosedherein. In some embodiments, the method for treating dry eye disease ina subject in need thereof may include administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin. The method may include administering a pharmaceuticalformulation to the eyelid. The method may also include administering thepharmaceutical formulation daily for at least 1 month.

In some embodiments, a method for treating blepharitis in a subject inneed thereof is disclosed and may include administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin. The method may include administering a pharmaceuticalformulation to the eyelid. The method may also include administering thepharmaceutical formulation daily for at least 1 month.

In other embodiments, a method for increasing secretion of meibum in asubject in need thereof is disclosed and may include administering tothe subject a pharmaceutical formulation comprising a sub-antibioticdose of azithromycin. The method may include administering apharmaceutical formulation to the eyelid. The method may also includeadministering the pharmaceutical formulation daily for at least 1 month.

In some embodiments, a method for treating dry eye disease in a subjectin need thereof comprises administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin. Themethod may include administering a pharmaceutical formulation to theeyelid. The method may also include administering the pharmaceuticalformulation daily for at least 1 month.

In some embodiments a method for treating blepharitis in a subject inneed thereof may include administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin. Themethod may include administering a pharmaceutical formulation to theeyelid. The method may also include administering the pharmaceuticalformulation daily for at least 1 month.

In other embodiments, a method for increasing secretion of meibum in asubject in need thereof may include administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin. The method may include administering a pharmaceuticalformulation to the eyelid. The method may also include administering thepharmaceutical formulation daily for at least 1 month.

In other embodiments, a method for treating dry eye disease orblepharitis in a subject in need thereof may include administering tothe subject a pharmaceutical formulation of azelaic acid. The method mayinclude administering a pharmaceutical formulation to the eyelid. Theadministration of such a pharmaceutical formulation may reduce a symptomof dry eye disease or blepharitis. The method may also includeadministering the pharmaceutical formulation daily for at least 1 month.

In other embodiments, a method for increasing secretion of meibum in asubject may include administering a pharmaceutical formulation ofazelaic acid. The method may include administering a pharmaceuticalformulation to the eyelid. The administration of such a pharmaceuticalformulation may reduce a symptom of inadequate tear production or poorquality of tears.

In other embodiments, a method for treating dry eye disease, treatingblepharitis, or increasing secretion of meibum in a subject in needthereof in a subject in need thereof may include administering to theeyelid of the subject a pharmaceutical formulation. The pharmaceuticalformulation may include between about 1% and about 20% azelaic acid. Thepharmaceutical formulation may include between about 0.1% to about 0.5%azithromycin. The method may further include administering thepharmaceutical formulation daily for at least a month.

Pharmaceutical formulations are also disclosed herein. In someembodiments, a pharmaceutical formulation for treating a condition ofthe eye may include a sub-antibiotic dose of azithromycin. Apharmaceutical formulation for treating a treating a condition of theeye may include a sub-antiparasitic dose of an avermectin.

In other embodiments, a pharmaceutical formulation for treating acondition of the eye may include a sub-antibiotic dose of azithromycinand a sub-antiparasitic dose of an avermectin. A pharmaceuticalformulation for treating a condition of the eye may include asub-antibiotic dose of azithromycin and a sub-antiparasitic dose of anavermectin and may further include an immunosuppressant.

In other embodiments, a pharmaceutical formulation for treating acondition of the eye may include a sub-antibiotic dose of azithromycinor a sub-antiparasitic dose of an avermectin, and azelaic acid.

DETAILED DESCRIPTION

The following description, for purposes of explanation, uses specificnomenclature to provide a thorough understanding of the invention.However, it will be apparent to one skilled in the art that specificdetails are not required in order to practice the invention. Thus, theforegoing descriptions of specific embodiments of the invention arepresented for purposes of illustration and description. They are notintended to be exhaustive or to limit the invention to the precise formsdisclosed; obviously, many modifications and embodiments are possible inview of the teachings disclosed herein.

Described herein are embodiments of pharmaceutical formulations andmethods for treating conditions of the eye. For example, pharmaceuticalformulations and methods such as those described herein may be used totreat dry eye disease (DED). In some embodiments, such formulations andmethods may be used to treat blepharitis. In some embodiments, theblepharitis is caused by demodex, while in other embodiments, theblepharitis is not caused by demodex. As another example, in someembodiments, such formulations and methods may be used to increase orenhance secretion of meibum. In some embodiments, such formulations andmethods may be used to increase secretion or enhance the quality ofmeibum.

As used herein, “treat” or “treating” a disease or condition may mean toreduce, alleviate, and/or eliminate one or more symptoms of the diseaseor condition. For instance, a method of treating dry eye diseasedisclosed herein may result in the reduction of one or more symptoms ofdry eye disease.

There are currently few effective, long-term formulations or methods oftreatment for conditions of the eye, such as dry eye disease andblepharitis. Commercially approved treatments are limited and targetspecific symptoms or causes, such as inflammation or bacterialinfection. In contrast, the formulations and methods described hereinprovide several advantages, including the ability to dose long term andto generally improve meibum quality and increase secretion in thoseindividuals who would benefit therefrom. Additional beneficial featuresare described in more detail below.

Pharmaceutical Formulations

Generally, in some embodiments, a pharmaceutical formulation fortreating a condition of the eye may include an antibiotic, anantiparasitic, and/or a dicarboxylic acid (e.g., azelaic acid). Forinstance, the antibiotic may be azithromycin. In particular, theseformulations may include a sub-antibiotic dose of an antibiotic such asazithromycin. “Sub-antibiotic”, as used herein, refers to an amount orconcentration of antibiotic agent that is below what is typicallyadministered to kill or inhibit the growth of bacteria, or an amount orconcentration of antibiotic agent that is below what is clinicallyuseful for killing or inhibiting growth of bacteria. For instance, asub-antibiotic amount of azithromycin may be below 1%. For sake ofclarity, percent of a component of a formulation described herein canmean w/v, w/w, or v/v percent. For example, “below 1%” can be read tomean below 1% weight/volume (% w/v), below 1% weight/weight (% w/w), orbelow 1% volume/volume (% v/v). In some embodiments, a pharmaceuticalformulation for treating a condition of the eye may include brimonidine,oxymetazoline, or metronidazole.

Notably, the sub-antibiotic formulations disclosed herein are contrastedwith commercial formulations of antibiotics that are used in ophthalmicapplications. For instance, AzaSite® and Klarity-A™ contain 1%azithromycin and are used to treat bacterial conjunctivitis, orinfections of the eye. Azyter® is another commercial ophthalmicformulation containing 1.5% azithromycin. However, formulations such asAzasite®, Klarity-A™, and Azyter® are not suitable chronic use. TheAzaSite label states that “prolonged use may result in overgrowth ofnon-susceptible organisms, including fungi,” potentially leading to newand more difficult-to-treat infections. Further, U.S. Pat. No. 8,349,806discloses an anti-inflammatory mechanism of action for AzaSite, however,in 2011, the FDA noted that claims that AzaSite had anti-inflammatoryproperties had never been clinically validated. Klarity-A™ listspossible adverse effects such as eye irritation, blurred vision, contactdermatitis, corneal erosion, decreased visual acuity, dysgeusia, eyepain, facial edema, eye reactions (burning sensation, eye discharge,stinging), nasal congestion, sinusitis, swelling of the eye, and skinrash.

In contrast to commercial antibiotic formulations, the sub-antibioticpharmaceutical formulations of this present disclosure are useful, andsafe, for long-term (e.g., at least one month, years) treatment ofchronic disorders of the eye that do not result from, for instance,infection or inflammation of tissue in or around the eye. Thecomparatively low doses of the sub-antibiotic formulations describedherein, instead, alter the meibum lipid chemistry, reduce the phasetransition temperature and melting point of meibum, and thereby helpliquefy, loosen, or soften hardened meibum at any temperature, includingat normal environmental, physiological, body, and eyelid temperatures,to ensure consistent natural meibum expression from the meibomian glandsonto the tear via the blink mechanism. In so doing, the healthy andprotective outermost lipid layer of tears are restored and fortified andthe accelerated, premature evaporation of tears is avoided. In so doing,the symptoms of chronic DED and blepharitis associated with obstructedmeibomian glands, hardened and unavailable meibum, or poor qualitymeibum can be alleviated. Additionally, in some embodiments, thepharmaceutical formulations can chronically maintain the quality ofmeibum secreted by healthy individuals, thus preventing MGD orMGD-related EDE. Previous studies have shown that antibiotic levels ofazithromycin (1%) can improve the phase transition temperature of meibumlipids and lipid ordering (Foulks, et al., Cornea, 2010, 29(7)).Pharmaceutical formulations disclosed herein may improve the phasetransition temperature of meibum lipids and lipid ordering at lowerconcentrations and for extended periods of time. The methods andformulations described herein may reduce a symptom of inadequate tearproduction or poor quality of tears. In some embodiments, a symptom ofinadequate tear production or poor quality of tears may be redness,stinging, burning, itching, light sensitivity, watery eyes, blurryvision, irregularities of the ocular surface, or damage to corneal orconjunctival epithelium and tissues. In some embodiments, thesub-antiparasitic pharmaceutical formulations may address posteriorblepharitis.

A pharmaceutical formulation for treating a condition of the eye maycomprise a dicarboxylic acid such as azelaic acid. Azelaic acid(nonanedioic acid) is a saturated dicarboxylic acid withanti-inflammatory properties that is used in commercial formulations forthe treatment of acne and rosacea. Approved commercial products such asFINACEA and AZELEX contain high concentrations (15% and 20%,respectively) of azelaic acid. Pharmaceutical formulations of thispresent disclosure comprising a dicarboxylic acid (e.g., azelaic acid)are useful, and safe, for long-term (e.g., at least one month, at leastsix months, at least one year) treatment of chronic disorders of the eyethat do not result from, for instance, infection or inflammation oftissue in or around the eye. Specifically, the pharmaceuticalformulations disclosed herein may act on the anterior eyelid to treatocular conditions such as MGD, MGD-related EDE, or blepharitis in, at,or around the orifice of the meibomian glands. Dicarboxylic acids (e.g.,azelaic acid) may also have anti-inflammatory, anti-oxidative,anti-bacterial, or anti-keratinizing properties that act complementaryto the treatment of anterior lid conditions. Dicarboxylic acids, whenused as described herein, may encourage cell turnover, promote removalof dead cells, decrease keratin at the lid margin, and/or assist inexfoliation of the lid margin, and may remedy the keratinization seen inMGD. Dicarboxylic acids may additionally function to kill demodex mitesand/or promote an environment sufficiently inhospitable for demodexmites, thus decreasing the likelihood of demodex mite survival. In someembodiments, the dicarboxylic acid (e.g., azelaic acid) may addressanterior blepharitis.

In the case of a dicarboxylic acid (e.g., azelaic acid), thepharmaceutical formulations described herein may comprise between about1% and about 20% of a dicarboxylic acid (e.g., azelaic acid). In someembodiments, the pharmaceutical formulation comprises between about 1%and 5%; 5% and 10%; 10% and 15%; or 15% and 20% dicarboxylic acid (e.g.,azelaic acid). In some embodiments, the pharmaceutical formulationcomprises between about 1% and 2%; 2% and 20%; 2% and 18%; 2% and 16%;2% and 14%; 2% and 12%; 2% and 10%; 2% and 8%; 2% and 6%; 2% and 4%; 4%and 20%; 4% and 18%; 4% and 16%; 4% and 14%; 4% and 12%; 4% and 10%; 4%and 8%; 4% and 6%; 6% and 20%; 6% and 18%; 6% and 16%; 6% and 14%; 6%and 12%; 6% and 10%; 6% and 8%; 8% and 20%; 8% and 18%; 8% and 16%; 8%and 14%; 8% and 12%; 8% and 10%; 10% and 20%; 10% and 18%; 10% and 16%;10% and 14%; 10% and 12%; 12% and 20%; 12% and 18%; 12% and 16%; 12% and14%; 14% and 20%; 14% and 18%; 14% and 16%; 16% and 20%; 16% and 18%; or18% and 20% dicarboxylic acid (e.g., azelaic acid). In some embodiments,the pharmaceutical formulation comprises about 1%, 2%, 3%, 4%, 5%, 6%,7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%dicarboxyclic acid (e.g., azelaic acid).

In some embodiments, a pharmaceutical formulation for treating acondition of the eye may include an antiparasitic. For instance, theantiparasitic may be an avermectin. In particular, these formulationsmay include a sub-antiparasitic dose of an antiparasitic such as anavermectin. “Sub-antiparasitic”, as used herein, refers to an amount orconcentration of antiparasitic agent that is below what is typicallyadministered to kill or inhibit the growth or reproduction of aparasite, or an amount or concentration of antibiotic agent that isbelow what is clinically useful for killing or inhibiting growth orreproduction of parasites.

The sub-antiparasitic formulations disclosed herein are contrasted withcommercial formulations of antibiotics that are used in ophthalmicapplications. For instance, a sub-antiparasitic amount of an avermectinmay be below 1%. In some embodiments, the sub-antiparasitic avermectinof the disclosed formulations may be ivermectin, selamectin, doramectin,eprinomectin, or abamectin. In some embodiments, the avermectin isivermectin.

Notably, the sub-antiparasitic formulations disclosed herein arecontrasted with commercial formulations of anti-parasitics. Forinstance, the commercial formulation Soolantra® is a topical 1%ivermectin cream used to treat rosacea. The FDA label specifies that itshould not be used for ophthalmic purposes. In one clinical trial (seehttps://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206255Orig1s000MedR.pdf),a 52 week open-label study with 1% ivermectin was stopped early at week10 due to abnormal laboratory findings, namely, low neutrophil counts.Notably, lower concentrations lose efficacy toward its intended rosaceatreatment (e.g., 0.1% and 0.35%). Additional safety concerns with 1%ivermectin cream include nasopharyngitis, headache, and upperrespiratory tract infection.

In contrast to topical anti-parasitic formulations, thesub-antiparasitic pharmaceutical formulations of the present disclosureare useful, and safe, for long-term (e.g., at least one month, years)treatment of chronic disorders of the eye that do not result from, forinstance, parasitic infection or inflammation of tissue in or around theeye. As described for the sub-antibiotic formulations above, thecomparatively low doses of the sub-antiparasitic formulations describedherein, instead, alter the meibum lipid chemistry and loosen or softenhardened meibum to ensure consistent natural expression from themeibomian glands. In so doing, the symptoms of chronic DED andblepharitis associated with obstructed glands, hardened and unavailablemeibum, or poor quality meibum can be alleviated. Additionally, in someembodiments, the pharmaceutical formulations can chronically maintainthe quality of meibum secreted by healthy individuals, thus preventingMGD or MGD-related EDE. In some embodiments, the sub-antiparasiticpharmaceutical formulations may address posterior blepharitis.

As described above, a sub-antibiotic formulation may have less than 1%of an antibiotic, and a sub-antiparasitic formulation may have less than1% of an antiparasitic. In some embodiments, the pharmaceuticalformulation comprises less than 1% azithromycin. In certain embodiments,the pharmaceutical formulation comprises 0.5% or less azithromycin. Incertain embodiments, the pharmaceutical formulation comprises 0.1% orless azithromycin. In certain embodiments, the pharmaceuticalformulation comprises 0.01% or less azithromycin. In certainembodiments, the pharmaceutical formulation comprises 0.001% or lessazithromycin. In certain embodiments, the pharmaceutical formulationcomprises about 0.5% azithromycin. In certain embodiments, thepharmaceutical formulation comprises about 0.1% azithromycin. In certainembodiments, the pharmaceutical formulation comprises about 0.01%azithromycin. In certain embodiments, the pharmaceutical formulationcomprises about 0.001% azithromycin. In certain embodiments, thepharmaceutical formulation comprises between about 0.5% and about 1%azithromycin. In certain embodiments, the pharmaceutical formulationcomprises between about 0.1% and about 1% azithromycin. In certainembodiments, the pharmaceutical formulation comprises between about0.01% and about 1% azithromycin. In certain embodiments, thepharmaceutical formulation comprises between about 0.001% and about 1%azithromycin. In certain embodiments, the pharmaceutical formulationcomprises between about 0.01% and about 0.1% azithromycin. In certainembodiments, the pharmaceutical formulation comprises between about0.001% and about 0.1% azithromycin. In certain embodiments, thepharmaceutical formulation comprises between about 0.001% and about0.01% azithromycin. In certain embodiments, the pharmaceuticalformulation comprises between about 0.4% and about 0.5% azithromycin. Incertain embodiments, the pharmaceutical formulation may further comprisea dicarboxylic acid (e.g., azelaic acid). The pharmaceutical formulationmay, for instance, comprise any concentration of azithromycin and anyconcentration of a dicarboxylic acid (e.g., azelaic acid) describedherein. In some embodiments, the pharmaceutical formulation comprisesbetween about 1% and about 20% a dicarboxylic acid (e.g., azelaic acid).In some embodiments, the pharmaceutical formulation comprises betweenabout 1% and 5%; 5% and 10%; 10% and 15%; or 15% and 20% a dicarboxylicacid (e.g., azelaic acid). In some embodiments, the pharmaceuticalformulation comprises between about 1% and 2%; 2% and 20%; 2% and 18%;2% and 16%; 2% and 14%; 2% and 12%; 2% and 10%; 2% and 8%; 2% and 6%; 2%and 4%; 4% and 20%; 4% and 18%; 4% and 16%; 4% and 14%; 4% and 12%; 4%and 10%; 4% and 8%; 4% and 6%; 6% and 20%; 6% and 18%; 6% and 16%; 6%and 14%; 6% and 12%; 6% and 10%; 6% and 8%; 8% and 20%; 8% and 18%; 8%and 16%; 8% and 14%; 8% and 12%; 8% and 10%; 10% and 20%; 10% and 18%;10% and 16%; 10% and 14%; 10% and 12%; 12% and 20%; 12% and 18%; 12% and16%; 12% and 14%; 14% and 20%; 14% and 18%; 14% and 16%; 16% and 20%;16% and 18%; or 18% and 20% a dicarboxylic acid (e.g., azelaic acid). Insome embodiments, the pharmaceutical formulation comprises about 1%, 2%,3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, or 20% dicarboxyclic acid (e.g., azelaic acid).

Table 1 shows exemplary formulations of a sub-antibiotic dose ofazithromycin in combination with azelaic acid.

TABLE 1 Exemplary formulations of a sub-antibiotic dose of azithromycinin combination with azelaic acid Sub-antibiotic dose of azithromycinAzelaic acid 0.4% azithromycin  5% azelaic acid 0.4% azithromycin 10%azelaic acid 0.4% azithromycin 15% azelaic acid 0.5% azithromycin  5%azelaic acid 0.5% azithromycin 10% azelaic acid 0.5% azithromycin 15%azelaic acid

In the case of sub-antiparasitic formulations, the pharmaceuticalformulation may have less than 1% of an avermectin. In certainembodiments, the pharmaceutical formulation comprises 0.5% or less of anavermectin. In certain embodiments, the pharmaceutical formulationcomprises 0.1% or less of an avermectin. In certain embodiments, thepharmaceutical formulation comprises 0.01% or less of an avermectin. Incertain embodiments, the pharmaceutical formulation comprises 0.001% orless of an avermectin. In certain embodiments, the pharmaceuticalformulation comprises about 0.5% of an avermectin. In certainembodiments, the pharmaceutical formulation comprises about 0.1% of anavermectin. In certain embodiments, the pharmaceutical formulationcomprises about 0.01% of an avermectin. In certain embodiments, thepharmaceutical formulation comprises about 0.001% of an avermectin. Incertain embodiments, the pharmaceutical formulation comprises betweenabout 0.5% and about 1% of an avermectin. In certain embodiments, thepharmaceutical formulation comprises between about 0.1% and about 1% ofan avermectin. In certain embodiments, the pharmaceutical formulationcomprises between about 0.01% and about 1% of an avermectin. In certainembodiments, the pharmaceutical formulation comprises between about0.001% and about 1% of an avermectin. In certain embodiments, thepharmaceutical formulation comprises between about 0.01% and about 0.1%of an avermectin. In certain embodiments, the pharmaceutical formulationcomprises between about 0.001% and about 0.1% of an avermectin. Incertain embodiments, the pharmaceutical formulation comprises betweenabout 0.001% and about 0.01% of an avermectin. In certain embodiments,the pharmaceutical formulation may further comprise a dicarboxylic acid(e.g., azelaic acid). The pharmaceutical formulation may, for instance,comprise any concentration of an avermectin and any concentration of adicarboxylic acid (e.g., azelaic acid) described herein. In someembodiments, the pharmaceutical formulation comprises between about 1%and about 20% dicarboxylic acid (e.g., azelaic acid). In someembodiments, the pharmaceutical formulation comprises between about 1%and 5%; 5% and 10%; 10% and 15%; or 15% and 20% dicarboxylic acid (e.g.,azelaic acid). In some embodiments, the pharmaceutical formulationcomprises between about 1% and 2%; 2% and 20%; 2% and 18%; 2% and 16%;2% and 14%; 2% and 12%; 2% and 10%; 2% and 8%; 2% and 6%; 2% and 4%; 4%and 20%; 4% and 18%; 4% and 16%; 4% and 14%; 4% and 12%; 4% and 10%; 4%and 8%; 4% and 6%; 6% and 20%; 6% and 18%; 6% and 16%; 6% and 14%; 6%and 12%; 6% and 10%; 6% and 8%; 8% and 20%; 8% and 18%; 8% and 16%; 8%and 14%; 8% and 12%; 8% and 10%; 10% and 20%; 10% and 18%; 10% and 16%;10% and 14%; 10% and 12%; 12% and 20%; 12% and 18%; 12% and 16%; 12% and14%; 14% and 20%; 14% and 18%; 14% and 16%; 16% and 20%; 16% and 18%; or18% and 20% a dicarboxylic acid (e.g., azelaic acid). In someembodiments, the pharmaceutical formulation comprises about 1%, 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, or 20% dicarboxyclic acid (e.g., azelaic acid).

A formulation of a sub-antibiotic dose of an antibiotic, or asub-antiparasitic dose of an anti-parasitic, as described above, may beon their own sufficient, and safe, for treating a chronic condition ofthe eye. However, in some instances it might be beneficial to applyformulations that combine both an antiparasitic and an antibiotic inorder to achieve a more robust effect. This increased effect might be aresult of synergy between the two agents in their ability to increasethe amount and/or quality of meibum produced. Similarly, such asynergistic effect may be obtained by combining azithromycin with adicarboxylic acid (e.g., azelaic acid) or ivermectin with a dicarboxylicacid (e.g., azelaic acid).

For instance, in some embodiments, the pharmaceutical formulation mayhave both azithromycin and an avermectin. In certain embodiments, thepharmaceutical formulation comprises a sub-antibiotic dose ofazithromycin and further comprises an avermectin. In certainembodiments, the pharmaceutical formulation comprises a sub-antibioticdose of azithromycin and further comprises 1% or more of an avermectin.In certain embodiments, the pharmaceutical formulation comprises asub-antiparasitic dose of an avermectin and further comprises 1% or moreazithromycin. In some embodiments, the pharmaceutical formulationcomprises a sub-antibiotic dose of azithromycin and further comprises asub-antiparasitic dose of an avermectin. In some embodiments, thepharmaceutical formulation comprises a sub-antibiotic dose ofazithromycin, a sub-antiparasitic dose of an avermectin, and a dose of adicarboxylic acid (e.g., azelaic acid).

The formulations of the present disclosure can be delivered by a topicalroute to the external surface of the eyelid. For instance, thepharmaceutical formulations may be applied (e.g., administered) viaapplicator sticks, contact lenses, ocular inserts, cul-de-sac inserts,fornix inserts, as solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, sprays, drops, andaerosols. The formulations of the present disclosure may additionallyinclude components to provide sustained release and/or comfort. Suchcomponents include high molecular weight, anionic mucomimetic polymers,gelling polysaccharides and finely-divided drug carrier substrates.Formulations may additionally be loaded onto a patch with an absorbableadhesive, or a fully or partially bioabsorbable patch, that is appliedto one or more of the eyelids.

One advantage of the pharmaceutical formulations disclosed herein isthat they may be applied directly to an eyelid, rather than be appliedsystemically. Application to the eyelids allows the formulation to mostdirectly reach the meibomian glands, where meibum amount and/or qualitycan be improved. To assist in penetration of the sub-antibiotic dose ofazithromycin, a sub-antiparasitic dose of an avermectin, and/or adicarboxylic acid (e.g., azelaic acid) through the eyelid to reach themeibomian glands, the pharmaceutical formulation may have at least oneskin penetration enhancer. In some embodiments, the skin penetrationenhancer is selected from polyethylene glycol, propylene glycol, sodiumlaurel sulfate, and a ceramide. In certain embodiments, thepharmaceutical formulation comprises about 0.1% to about 5% of the skinpenetration enhancer. In certain embodiments, the pharmaceuticalformulation comprises about 0.1% to about 1% of the skin penetrationenhancer. In certain embodiments, the pharmaceutical formulationcomprises about 0.1% to about 0.25% of the skin penetration enhancer. Incertain embodiments, the pharmaceutical formulation comprises about 1%to about 5% of the skin penetration enhancer. In certain embodiments,the pharmaceutical formulation comprises about 1% to about 4% of theskin penetration enhancer. In certain embodiments, the pharmaceuticalformulation comprises about 1% to about 3% of the skin penetrationenhancer. In certain embodiments, the pharmaceutical formulationcomprises about 1% to about 2% of the skin penetration enhancer. Incertain embodiments, the pharmaceutical formulation comprises about 2%to about 5% of the skin penetration enhancer. In certain embodiments,the pharmaceutical formulation comprises about 2% to about 4% of theskin penetration enhancer. In certain embodiments, the pharmaceuticalformulation comprises about 2% to about 3% of the skin penetrationenhancer. In certain embodiments, the pharmaceutical formulationcomprises about 3% to about 5% of the skin penetration enhancer. Incertain embodiments, the pharmaceutical formulation comprises about 3%to about 4% of the skin penetration enhancer.

Exemplary formulations of a sub-antibiotic dose of azithromycin incombination with a skin penetration enhancer are shown in Table 2.

TABLE 2 Exemplary formulations of a sub-antibiotic dose of azithromycinin combination with a skin penetration enhancer Azithromycin CompositionSkin Penetration Enhancer Sub-antibiotic azithromycin 0.5-4%polyethylene glycol Sub-antibiotic azithromycin 0.5-4% propylene glycolSub-antibiotic azithromycin 1% sodium laurel sulfate and a ceramideSub-antibiotic azithromycin 0.5-4% polyethylene glycol, 0.5-4% propyleneglycol, 1% sodium laurel sulfate, and a ceramide Sub-antibioticazithromycin 0.5% polyethylene glycol and 0.5% propylene glycolSub-antibiotic azithromycin 0.25% polyethylene glycol and 0.25%propylene glycol

Exemplary formulations of azelaic acid in combination with a skinpenetration enhancer are shown in Table 3.

TABLE 3 Exemplary formulations of a sub-antibiotic dose of azelaic acidin combination with a skin penetration enhancer Azelaic Acid CompositionSkin Penetration Enhancer  5% azelaic acid 0.5-4% polyethylene glycol 5% azelaic acid 0.5-4% propylene glycol  5% azelaic acid 1% sodiumlaurel sulfate and a ceramide  5% azelaic acid 0.5-4% polyethyleneglycol, 0.5-4% propylene glycol, 1% sodium laurel sulfate, and aceramide  5% azelaic acid 0.5% polyethylene glycol and 0.5% propyleneglycol  5% azelaic acid 0.25% polyethylene glycol and 0.25% propyleneglycol 10% azelaic acid 0.5-4% polyethylene glycol 10% azelaic acid0.5-4% propylene glycol 10% azelaic acid 1% sodium laurel sulfate and aceramide 10% azelaic acid 0.5-4% polyethylene glycol, 0.5-4% propyleneglycol, 1% sodium laurel sulfate, and a ceramide 10% azelaic acid 0.5%polyethylene glycol and 0.5% propylene glycol 10% azelaic acid 0.25%polyethylene glycol and 0.25% propylene glycol 15% azelaic acid 0.5-4%polyethylene glycol 15% azelaic acid 0.5-4% propylene glycol 15% azelaicacid 1% sodium laurel sulfate and a ceramide 15% azelaic acid 0.5-4%polyethylene glycol, 0.5-4% propylene glycol, 1% sodium laurel sulfate,and a ceramide 15% azelaic acid 0.5% polyethylene glycol and 0.5%propylene glycol 15% azelaic acid 0.25% polyethylene glycol and 0.25%propylene glycol

Exemplary formulations of a sub-antibiotic dose of an avermectin incombination with a skin penetration enhancer are shown in Table 4.

TABLE 4 Exemplary formulations of a sub-antiparasitic dose of anavermectin in combination with a skin penetration enhancer AvermectinComposition Skin Penetration Enhancer Sub-antiparasitic ivermectin0.5-4% polyethylene glycol Sub-antiparasitic ivermectin 0.5-4% propyleneglycol Sub-antiparasitic ivermectin 1% sodium laurel sulfate and aceramide Sub-antiparasitic ivermectin 0.5-4% polyethylene glycol, 0.5-4%propylene glycol, 1% sodium laurel sulfate, and a ceramideSub-antiparasitic ivermectin 0.5% polyethylene glycol and 0.5% propyleneglycol Sub-antiparasitic ivermectin 0.25% polyethylene glycol and 0.25%propylene glycol

In some embodiments, the formulations described herein may contain atleast one polyol. Therefore, adding a polyol to a formulation describedherein may increase solubility of one or more component described herein(e.g., azithromycin, azelaic acid). In some embodiments, the polyol ispropylene glycol, polyethylene glycol, glycerol, erythritol, mannitol,or sorbitol. In certain embodiments, the pharmaceutical formulationcomprises about 0.1% to about 20% of the polyol. In certain embodiments,the pharmaceutical formulation comprises about 0.1% to about 15% of thepolyol. In certain embodiments, the pharmaceutical formulation comprisesabout 0.1% to about 10% of the polyol. In certain embodiments, thepharmaceutical formulation comprises about 0.1% to about 5% of thepolyol. In certain embodiments, the pharmaceutical formulation comprisesabout 1% to about 20% of the polyol. In certain embodiments, thepharmaceutical formulation comprises about 1% to about 15% of thepolyol. In certain embodiments, the pharmaceutical formulation comprisesabout 1% to about 10% of the polyol. In certain embodiments, thepharmaceutical formulation comprises about 1% to about 5% of the polyol.In certain embodiments, the pharmaceutical formulation comprises about1% to about 4%; about 4% to about 20%; about 4% to about 16%; about 4%to about 12%; about 4% to about 8%; 8% to about 20%; about 8% to about16%; about 8% to about 12%; about 12% to about 20%; about 12% to about16%; or about 16% to about 20%; of the polyol. In certain embodiments,the pharmaceutical formulation comprises about 1%, 2%, 3%, 4%, 5%, 6%,7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% ofthe polyol.

Exemplary formulations of a sub-antibiotic dose of azithromycin andazelaic acid in combination with a polyol are shown in Table 5.

TABLE 5 Exemplary formulations of a sub-antibiotic dose of azithromycinand azelaic acid in combination with a polyol suitable for treatingconditions of the eye Azithromycin Azelaic acid Polyol About 0.1%-0.5%About 1%-20% About 1%-10% propylene azithromycin azelaic acid glycolAbout 0.1%-0.5% About 5%-20% About 1%-10% propylene azithromycin azelaicacid glycol About 0.4%-0.5% About 5%-15% About 1%-10% propyleneazithromycin azelaic acid glycol About 0.4% About 10% About 8% propyleneazithromycin azelaic acid glycol

In some instances, it is beneficial to administer a sub-antibiotic doseof azithromycin, a sub-antiparasitic dose of an avermectin, and/or adicarboxylic acid (e.g., azelaic acid) together with animmunosuppressant. In this way, improvement of meibum amount and/orquality may be achieved by the azithromycin, avermectin, and/or adicarboxylic acid (e.g., azelaic acid), and additional improvement ininflammatory aspects of the condition of the eye may be concomitantlyachieved by the immunosuppressant. Disclosed formulations may be usefulin treating ADDE and EDE simultaneously. In some embodiments, thepharmaceutical formulation comprises an immunosuppressant. In certainembodiments, the immunosuppressant is selected from the group consistingof cyclosporine, tacrolimus, and lifitegrast. In certain embodiments,the immunosuppressant is cyclosporine. In certain embodiments, theimmunosuppressant is tacrolimus. In certain embodiments, theimmunosuppressant is lifitegrast. In certain embodiments, thepharmaceutical formulation comprises less than about 1% of animmunosuppressant. In certain embodiments, the pharmaceuticalformulation comprises about 0.01% to about 5% of an immunosuppressant.In certain embodiments, the pharmaceutical formulation comprises about0.01% to about 0.1% of an immunosuppressant. In certain embodiments, thepharmaceutical formulation comprises about 0.01% to about 0.05% of animmunosuppressant. In certain embodiments, the pharmaceuticalformulation comprises about 0.05% to about 0.1% of an immunosuppressant.In certain embodiments, the pharmaceutical formulation comprises about0.1% to about 5% of an immunosuppressant. In certain embodiments, thepharmaceutical formulation comprises about 1% of an immunosuppressant.In certain embodiments, the pharmaceutical formulation comprises about5% of an immunosuppressant.

In some embodiments, the pharmaceutical formulation comprises one ormore additional agent selected from the group consisting of brimonidine,isotretinoin, cyclosporine, hypochlorous acid, and tea tree oil.

Additionally or alternatively, the pharmaceutical formulations disclosedherein may be suitable for treating dermatologic conditions, includingrosacea and acne, independent of age (i.e., for all age groups).

In some embodiments of the pharmaceutical formulation disclosed herein,the formulation may contain one or more additional pharmaceuticallyacceptable carriers. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs,” M. E.Aulton, Churchill Livingstone, 1988, which is hereby incorporated byreference in its entirety.

The term “carrier”, as used herein, may encompass carriers, excipients,and diluents and may mean a material, formulation or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a pharmaceutical agent,such as one or more crystalline forms of the disclosure, from one organ,or portion of the body, to another organ, or portion of the body of asubject. Carriers should be selected on the basis of compatibility andthe release profile properties of the desired dosage form. Exemplarycarrier materials may include, e.g., binders, suspending agents,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, wetting agents, diluents, spray-drieddispersions, and the like. See, e.g., Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975.

In some embodiments, the formulations described herein may containmineral oil and/or petrolatum.

In some embodiments, the agents described herein, alone or as part of apharmaceutical formulation, are also understood to include anypharmaceutically acceptable salt, solvate, tautomer, isotope, or isomerthereof.

Methods of Treating a Disorder

As described above, the formulations disclosed herein can be appliedsafely and chronically to treat disorders of the eye. Unlikecommercially available, higher concentration antibiotics orantiparasitic formulations indicated for their intended antibiotic orantiparasitic purposes, which can only be applied to the eye acutely, orcannot be applied to the eye at all, the present sub-antibiotic andsub-antiparasitic formulations, and formulations comprising adicarboxylic acid (e.g., azelaic acid), target the meibomian glandsdirectly, restore natural meibum lipid chemistry, restore natural meibummelting temperatures, and thereby improve the amount and/or quality ofmeibum produced and available to coat the outermost lipid layer of tearschronically. Methods described herein may reduce a symptom of inadequatetear production or poor quality of tears. In some embodiments, a symptomof inadequate tear production or poor quality of tears may be redness,stinging, burning, itching, light sensitivity, watery eyes, blurryvision, irregularities of the ocular surface, or damage to corneal orconjunctival epithelium and tissues. Formulations of the presentinvention may be safely applied daily for extended periods of time.

Chronic application could, for instance, involve application of thedisclosed pharmaceutical formulation over the course of at least amonth. Notably, the formulations could be applied for significantlylonger than one month. For instance, the formulations may be applied forat least 2 months, 6 months, 1 years, 2 years, 3 years, 4 years, 5years, 10 years, or longer. This directly benefits patients who sufferfrom chronic or congenital DED or blepharitis, or who otherwise needimproved meibum quality, and is not achievable with existing commercialformulations discussed previously.

Specifically, the pharmaceutical formulations disclosed herein may beadministered (e.g., applied) daily for at least 1 month. In someembodiments, the pharmaceutical formulation is administered daily for atleast 2 months. In some embodiments, the pharmaceutical formulation isadministered daily for at least 3 months. In some embodiments, thepharmaceutical formulation is administered daily for at least 4 months.In some embodiments, the pharmaceutical formulation is administereddaily for at least 5 months. In some embodiments, the pharmaceuticalformulation is administered daily for at least 6 months. In someembodiments, the pharmaceutical formulation is administered daily for atleast 7 months. In some embodiments, the pharmaceutical formulation isadministered daily for at least 8 months. In some embodiments, thepharmaceutical formulation is administered daily for at least 9 months.In some embodiments, the pharmaceutical formulation is administereddaily for at least 10 months. In some embodiments, the pharmaceuticalformulation is administered daily for at least 11 months. In someembodiments, the pharmaceutical formulation is administered daily for atleast 1 year. In some embodiments, the pharmaceutical formulation isadministered daily for at least 2 years. In some embodiments, thepharmaceutical formulation is administered daily for at least 3 years.In some embodiments, the pharmaceutical formulation is administereddaily for at least 4 months. In some embodiments, the pharmaceuticalformulation is administered daily for at least 5 years.

The pharmaceutical formulations disclosed herein may also beadministered every other day. In some embodiments, the pharmaceuticalformulation is administered daily every other week (e.g., one week ofadministration, followed by one week without administration). In someembodiments, the pharmaceutical formulation is administered daily everyother month.

In the methods disclosed herein, the daily administration of apharmaceutical formulation may mean once per day (i.e., once daily). Insome cases, it might be beneficial to apply the pharmaceuticalformulation more than once per day. In these cases, daily could meantwice a day (i.e., twice daily), three times a day, four times a day, ormore.

Generally, a method for treating a condition of the eye in a subject inneed thereof may include administering one or more compounds orpharmaceutical formulations described herein. In certain embodiments, amethod for treating dry eye disease in a subject in need thereof mayinclude administering one or more compounds or pharmaceuticalformulations described herein. In some embodiments, a method fortreating blepharitis in a subject in need thereof may includeadministering one or more compounds or pharmaceutical formulationsdescribed herein

In some embodiments, provided herein is the use of one or more compoundsor pharmaceutical formulations described herein in the manufacture of amedicament for treating a disorder. In some embodiments, provided hereinis the use of one or more compounds or pharmaceutical formulationsdescribed herein in the manufacture of a medicament for treating acondition of the eye. In some embodiments, provided herein is the use ofone or more compounds or pharmaceutical formulations described herein inthe manufacture of a medicament for treating dry eye disease. In someembodiments, provided herein is the use of one or more pharmaceuticalcompounds or pharmaceutical formulations described herein in themanufacture of a medicament for treating blepharitis. In someembodiments, provided herein is the use of one or more compounds orpharmaceutical formulations described herein in the manufacture of amedicament for increasing secretion of meibum.

In some embodiments, provided herein is the use of one or more compoundsor pharmaceutical formulations described herein as a medicament fortreating a disorder. In some embodiments, provided herein is the use ofone or more compounds or pharmaceutical formulations described herein asa medicament for treating a condition of the eye. In some embodiments,provided herein is the use of one or more compounds or pharmaceuticalformulations described herein as a medicament for treating dry eyedisease. In some embodiments, provided herein is the use of one or morepharmaceutical compounds or pharmaceutical formulations described hereinas a medicament for treating blepharitis. In some embodiments, providedherein is the use of one or more compounds or pharmaceuticalformulations described herein as a medicament for increasing secretionof meibum.

In some embodiments, provided herein is the use of one or more compoundsor pharmaceutical formulations described herein for treating a disorder.In some embodiments, provided herein is the use of one or more compoundsor pharmaceutical formulations described herein for treating a conditionof the eye. In some embodiments, provided herein is the use of one ormore compounds or pharmaceutical formulations described herein fortreating dry eye disease. In some embodiments, provided herein is theuse of one or more pharmaceutical compounds or pharmaceuticalformulations described herein for treating blepharitis. In someembodiments, provided herein is the use of one or more compounds orpharmaceutical formulations described herein for increasing secretion ofmeibum.

The methods described herein might be useful in treating any conditionof the eye for which the amount of meibum produced, or for which thequality of meibum produced, is reduced. Generally, this could beachieved through the application of a sub-antibiotic dose of anantibiotic. In some embodiments, provided herein is a method fortreating a condition of the eye in a subject in need thereof. In someembodiments, provided herein is a method for treating a condition of theeye in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a sub-antibiotic dose ofan antibiotic. In some embodiments, provided herein is a method fortreating a condition of the eye in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antibiotic dose of an antibiotic, wherein; (a) the pharmaceuticalformulation is administered to the eyelid, and (b) the pharmaceuticalformulation is administered daily for at least 1 month.

Similarly, general conditions of the eye for which meibum quantity orquality is impacted may be treated by the methods disclosed herein,whereby a sub-antiparasitic dose of an antiparasitic is applied. In someembodiments, provided herein is a method for treating a condition of theeye in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a sub-antiparasitic doseof an antiparasitic. In some embodiments, provided herein is a methodfor treating a condition of the eye in a subject in need thereof,comprising administering to the subject a pharmaceutical formulationcomprising a sub-antiparasitic dose of an antiparasitic, wherein; (a)the pharmaceutical formulation is administered to the eyelid, and (b)the pharmaceutical formulation is administered daily for at least 1month.

Similarly, general conditions of the eye for which meibum quantityand/or quality is impacted may be treated by the methods disclosedherein, whereby a dicarboxylic acid (e.g., azelaic acid) is applied. Insome embodiments, provided herein is a method for treating a conditionof the eye in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a dicarboxylic acid(e.g., azelaic acid). In some embodiments, provided herein is a methodfor treating a condition of the eye in a subject in need thereof,comprising administering to the subject a pharmaceutical formulationcomprising a dicarboxylic acid (e.g., azelaic acid), wherein; (a) thepharmaceutical formulation is administered to the eyelid, and (b) thepharmaceutical formulation is administered daily for at least 1 month.

In some embodiments, the antibiotic applied in a sub-antibiotic dose maybe azithromycin. In some embodiments, provided herein is a method fortreating a condition of the eye in a subject in need thereof. In someembodiments, provided herein is a method for treating a condition of theeye in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin. In some embodiments, provided herein is a method fortreating a condition of the eye in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antibiotic dose of azithromycin, wherein; (a) the pharmaceuticalformulation is administered to the eyelid, and (b) the pharmaceuticalformulation is administered daily for at least 1 month. In someembodiments, the sub-antibiotic dose of azithromycin may addressposterior blepharitis.

Alternatively, the antiparasitic applied in a sub-antiparasitic dose maybe an avermectin. In some embodiments, provided herein is a method fortreating a condition of the eye in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antiparasitic dose of an avermectin. In some embodiments, providedherein is a method for treating a condition of the eye in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein; (a) the pharmaceutical formulation is administered to theeyelid, and (b) the pharmaceutical formulation is administered daily forat least 1 month. In some embodiments, the sub-antiparasitic dose of anavermectin may address posterior blepharitis.

A method for treating a condition of the eye comprising administering tothe subject a pharmaceutical formulation comprising: a) a sub-antibioticdose of azithromycin; b) a sub-antiparasitic dose of an avermectin; c) asub-antibiotic dose of azithromycin and a sub-antiparasitic dose of anavermectin; d) a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising animmunosuppressant; e) a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising azelaicacid; or f) azelaic acid. In some embodiments, the pharmaceuticalformulation is applied to the eyelid daily for at least 1 month. In someembodiments of any of the methods described herein, the condition of theeye is one or more of dry eye disease, blepharitis, and meibomian glanddysfunction.

As described above, DED can result from or be caused by negativelyimpacted meibum amount or quality. DED therefore can be treated by theformulations of this invention, via the improvement of meibum amount orquality. In some embodiments, provided herein is a method for treatingdry eye disease in a subject in need thereof. In some embodiments,provided herein is a method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of an antibiotic. In someembodiments, provided herein is a method for treating dry eye disease ina subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose of anantibiotic, wherein; (a) the pharmaceutical formulation is administeredto the eyelid, and (b) the pharmaceutical formulation is administereddaily for at least 1 month. In some embodiments, provided herein is amethod for treating dry eye disease by lowering the melting temperatureof meibum. Methods of treating dry eye disease in a subject in needthereof may comprise administering a pharmaceutical formulationcomprising a sub-antibiotic dose of an antibiotic, and furthercomprising a dicarboxylic acid (e.g., azelaic acid).

Alternatively, but via similar mechanisms, DED can be treated usingsub-antiparasitic doses of antiparasitics. In some embodiments, providedherein is a method for treating dry eye disease in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an antiparasitic. Insome embodiments, provided herein is a method for treating dry eyedisease in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a sub-antiparasitic doseof an antiparasitic, wherein; (a) the pharmaceutical formulation isadministered to the eyelid, and (b) the pharmaceutical formulation isadministered daily for at least 1 month. Methods of treating dry eyedisease in a subject in need thereof may comprise administering apharmaceutical formulation comprising a sub-antiparasitic dose of anantiparasitic and a dicarboxylic acid (e.g., azelaic acid).

In some embodiments, provided herein is a method for treating dry eyedisease in a subject in need thereof. In some embodiments, providedherein is a method for treating dry eye disease in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin. In someembodiments, provided herein is a method for treating dry eye disease ina subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin, wherein; (a) the pharmaceutical formulation isadministered to the eyelid, and (b) the pharmaceutical formulation isadministered daily for at least 1 month. Methods of treating dry eyedisease in a subject in need thereof may comprise administering apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin and a dicarboxylic acid (e.g., azelaic acid).

In some embodiments, the methods for treating dry eye disease disclosedherein comprise administering to an external surface of an eyelid of asubject a pharmaceutical formulation described herein, whereinadministering the pharmaceutical formulation reduces a condition of dryeye disease. In some embodiments, a condition of dry eye disease may bemeibomian gland dysfunction, redness, stinging, burning, itching, lightsensitivity, watery eyes, blurry vision, irregularities of the ocularsurface, or damage to corneal or conjunctival epithelium and tissues.

In some embodiments, provided herein is a method for treating dry eyedisease in a subject in need thereof, comprising administering to thesubject a pharmaceutical formulation comprising a sub-antiparasitic doseof an avermectin. In some embodiments, provided herein is a method fortreating dry eye disease in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antiparasitic dose of an avermectin, wherein; (a) the pharmaceuticalformulation is administered to the eyelid, and (b) the pharmaceuticalformulation is administered daily for at least 1 month. In someembodiments, the avermectin is ivermectin.

In some embodiments, provided herein is a method for treating dry eyedisease in a subject in need thereof. In some embodiments, providedherein is a method for treating dry eye disease in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a dicarboxylic acid (e.g., azelaic acid). In someembodiments, provided herein is a method for treating dry eye disease ina subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a dicarboxylic acid (e.g., azelaicacid), wherein; (a) the pharmaceutical formulation is administered tothe eyelid, and (b) the pharmaceutical formulation is administered dailyfor at least 1 month

Methods for treating dry eye disease described herein may benefit fromalternating administration of a two or more pharmaceutical formulationsdescribed herein. Thus, in some embodiments, a method for treating dryeye disease in a subject in need thereof, comprises alternatingadministration of a first pharmaceutical formulation and a secondpharmaceutical formulation to the eyelid. In some embodiments, the firstpharmaceutical formulation comprises a sub-antibiotic dose ofazithromycin and is applied daily and the second pharmaceuticalformulation comprises a sub-antiparasitic dose of an avermectin and isapplied daily. In some embodiments, the first pharmaceutical formulationcomprises a sub-antibiotic dose of azithromycin and is applied daily andthe second pharmaceutical formulation comprises a dicarboxylic acid(e.g., azelaic acid) and is applied daily. In some embodiments, thefirst pharmaceutical formulation comprises a sub-antiparasitic dose ofivermectin and is applied daily and the second pharmaceuticalformulation comprises a dicarboxylic acid (e.g., azelaic acid) and isapplied daily.

Administration of the two pharmaceutical formulations may be alternateddaily, weekly, monthly, or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12months. In some embodiments, the alternating administration comprisesalternating the first and second pharmaceutical formulations daily(e.g., administering a first pharmaceutical formulation to the eyelid onday 1, administering a second pharmaceutical formulation to the eyelidon day 2, administering the first pharmaceutical formulation to theeyelid on day 3, and so on). In some embodiments, the alternatingadministration comprises alternating the first and second pharmaceuticalformulations monthly (e.g., administering a first pharmaceuticalformulation to the eyelid as described herein for a first month,administering a second pharmaceutical formulation to the eyelid asdescribed herein for a second month, administering the firstpharmaceutical formulation to the eyelid as described herein for a thirdmonth, and so on). In some embodiments, the alternating administrationcomprises alternating the first and second pharmaceutical formulationsevery two months.

As described previously, DED can be described as an umbrella termencompassing several sub-disorders. In some embodiments, the dry eyedisease is ADDE. In some embodiments, the dry eye disease is EDE. Insome embodiments, the dry eye disease is ADDE and EDE. The methods fortreating dry eye disease disclosed herein may treat ADDE and EDEsimultaneously.

DED is sometimes associated with underlying factors. One of thesefactors may be age. In certain embodiments, the dry eye disease isassociated with biological sex. In certain embodiments, the dry eyedisease is associated with an autoimmune disease. In certainembodiments, the dry eye disease is associated with medications takenfor other indications. In certain embodiments, the dry eye disease isassociated with the use of medical devices. In certain embodiments, thedry eye disease is associated with contact lenses. In certainembodiments, the dry eye disease is associated with environment. Incertain embodiments, the dry eye disease is associated with laser eyesurgery. In certain embodiments, the dry eye disease is associated withcataract surgery. In certain embodiments, the dry eye disease isassociated with smoking. In certain embodiments, the dry eye disease isassociated with overuse of screens, such as those of smart phones,computers, tablets, and the like. In some embodiments, the dry eyedisease is associated with a mucin deficiency.

In general, the methods disclosed herein may involve application of asub-antibiotic dose of an antibiotic, useful for treating blepharitis ina subject in need thereof. In some embodiments, provided herein is amethod for treating blepharitis in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antibiotic dose of an antibiotic. In some embodiments, providedherein is a method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of an antibiotic, wherein;(a) the pharmaceutical formulation is administered to the eyelid, and(b) the pharmaceutical formulation is administered daily for at least 1month. Methods of treating blepharitis in a subject in need thereof maycomprise administering a pharmaceutical formulation comprising asub-antibiotic dose of an antibiotic, further comprising a dicarboxylicacid (e.g., azelaic acid).

Alternatively, a method for treating blepharitis in a subject in needthereof may involve administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an antiparasitic. Insome embodiments, provided herein is a method for treating blepharitisin a subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anantiparasitic, wherein; (a) the pharmaceutical formulation isadministered to the eyelid, and (b) the pharmaceutical formulation isadministered daily for at least 1 month. Methods of treating blepharitisin a subject in need thereof may comprise administering a pharmaceuticalformulation comprising a sub-antiparasitic dose of an antiparasitic,further comprising a dicarboxylic acid (e.g., azelaic acid).

Additionally, a method for treating blepharitis in a subject in needthereof may involve administering to the subject a pharmaceuticalformulation comprising a dicarboxylic acid (e.g., azelaic acid). In someembodiments, provided herein is a method for treating blepharitis in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a dicarboxylic acid (e.g., azelaicacid), wherein; (a) the pharmaceutical formulation is administered tothe eyelid, and (b) the pharmaceutical formulation is administered dailyfor at least 1 month.

Methods for treating blepharitis described herein may benefit fromalternating administration of a two or more pharmaceutical formulationsdescribed herein. Thus, in some embodiments, a method for treatingblepharitis in a subject in need thereof, comprises alternatingadministration of a first pharmaceutical formulation and a secondpharmaceutical formulation to the eyelid. In some embodiments, the firstpharmaceutical formulation comprises a sub-antibiotic dose ofazithromycin and is applied daily and the second pharmaceuticalformulation comprises a sub-antiparasitic dose of an avermectin and isapplied daily. In some embodiments, the first pharmaceutical formulationcomprises a sub-antibiotic dose of azithromycin and is applied daily andthe second pharmaceutical formulation comprises a sub-antiparasitic doseof a dicarboxylic acid (e.g., azelaic acid) and is applied daily. Insome embodiments, the first pharmaceutical formulation comprises asub-antiparasitic dose of ivermectin and is applied daily and the secondpharmaceutical formulation comprises a sub-antiparasitic dose of adicarboxylic acid (e.g., azelaic acid) and is applied daily.Administration of the two pharmaceutical formulations may be alternateddaily, weekly, monthly, or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12months. In some embodiments, the alternating administration comprisesalternating the first and second pharmaceutical formulations daily. Insome embodiments, the alternating administration comprises alternatingthe first and second pharmaceutical formulations monthly. In someembodiments, the alternating administration comprises alternating thefirst and second pharmaceutical formulations every two months.

In some embodiments, the antibiotic applied in a sub-antibiotic dose totreat blepharitis may be azithromycin. In some embodiments, providedherein is a method for treating blepharitis in a subject in needthereof. In some embodiments, provided herein is a method for treatingblepharitis in a subject in need thereof, comprising administering tothe subject a pharmaceutical formulation comprising a sub-antibioticdose of azithromycin. In some embodiments, provided herein is a methodfor treating blepharitis in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antibiotic dose of azithromycin, wherein; (a) the pharmaceuticalformulation is administered to the eyelid, and (b) the pharmaceuticalformulation is administered daily for at least 1 month. Methods oftreating blepharitis in a subject in need thereof may compriseadministering a pharmaceutical formulation comprising a sub-antibioticdose of azithromycin, further comprising a dicarboxylic acid (e.g.,azelaic acid).

The methods described herein might be useful for treating both anteriorblepharitis and posterior blepharitis simultaneously. In someembodiments, anterior blepharitis and posterior blepharitis are treatedby administration of a single pharmaceutical formulation. In certainembodiments, anterior blepharitis and posterior blepharitis are treatedwith alternating administration of a first pharmaceutical formulationand a second pharmaceutical formulation. In some embodiments, thedicarboxylic acid (e.g., azelaic acid) addresses anterior blepharitisand the sub-antibiotic dose of azithromycin addresses posteriorblepharitis. In certain embodiments, the dicarboxylic acid (e.g.,azelaic acid) and the sub-antiparasitic dose of azithromycin are part ofa single formulation. In certain embodiments, the dicarboxylic acid(e.g., azelaic acid) and the sub-antibiotic dose of an azithromycin areseparate formulations.

Alternatively, the antiparasitic applied in a sub-antiparasitic dose totreat blepharitis may be an avermectin. In some embodiments, providedherein is a method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin. Insome embodiments, provided herein is a method for treating blepharitisin a subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin, wherein; (a) the pharmaceutical formulation is administeredto the eyelid, and (b) the pharmaceutical formulation is administereddaily for at least 1 month. Methods of treating blepharitis in a subjectin need thereof may comprise administering a pharmaceutical formulationcomprising a sub-antiparasitic dose of an avermectin, further comprisinga dicarboxylic acid (e.g., azelaic acid). In some embodiments, theavermectin is ivermectin.

The methods described herein might be useful for treating both anteriorblepharitis and posterior blepharitis simultaneously. In someembodiments, anterior blepharitis and posterior blepharitis are treatedby administration of a single pharmaceutical formulation. In certainembodiments, anterior blepharitis and posterior blepharitis are treatedwith alternating administration of a first pharmaceutical formulationand a second pharmaceutical formulation. In some embodiments, thedicarboxylic acid (e.g., azelaic acid) addresses anterior blepharitisand the sub-antiparasitic dose of an antiparasitic addresses posteriorblepharitis. In certain embodiments, the dicarboxylic acid (e.g.,azelaic acid) and the sub-antiparasitic dose of an antiparasitic arepart of a single formulation. In certain embodiments, the dicarboxylicacid (e.g., azelaic acid) and the sub-antiparasitic dose of anantiparasitic are separate formulations.

As described above, blepharitis might describe several sub-conditions.In some embodiments, the blepharitis is anterior blepharitis. In someembodiments, the blepharitis is posterior blepharitis. In someembodiments, the blepharitis is anterior and posterior blepharitis.

Generally, the methods described herein might be useful for increasingsecretion of meibum. The increase of meibum may, for instance, resultfrom the disclosed formulations improving meibum amount or quality byaltering the lipid chemistry, lowering the meibum melting temperature,or liquefying hardened meibum. In some embodiments, provided herein is amethod for increasing secretion of meibum in a subject in need thereof.In some embodiments, provided herein is a method for increasingsecretion of meibum in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antibiotic dose of an antibiotic. In some embodiments, providedherein is a method for increasing secretion of meibum in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of an antibiotic, wherein;(a) the pharmaceutical formulation is administered to the eyelid, and(b) the pharmaceutical formulation is administered daily for at least 1month. Methods for increasing secretion of meibum in a subject in needthereof may comprise administering a pharmaceutical formulationcomprising a sub-antibiotic dose of an antibiotic, further comprising adicarboxylic acid (e.g., azelaic acid). In certain embodiments, meibumfluidity is increased. In some embodiments, meibum melting temperatureis lowered.

In some embodiments, provided herein is a method for increasingsecretion of meibum in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antiparasitic dose of an antiparasitic. In some embodiments,provided herein is a method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anantiparasitic, wherein; (a) the pharmaceutical formulation isadministered to the eyelid, and (b) the pharmaceutical formulation isadministered daily for at least 1 month. Methods for increasingsecretion of meibum in a subject in need thereof may compriseadministering a sub-antiparasitic dose of an antiparasitic, furthercomprising a dicarboxylic acid (e.g., azelaic acid).

In some embodiments, provided herein is a method for increasingsecretion of meibum in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising adicarboxylic acid (e.g., azelaic acid). In some embodiments, providedherein is a method for increasing secretion of meibum in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a dicarboxylic acid (e.g., azelaic acid),wherein; (a) the pharmaceutical formulation is administered to theeyelid, and (b) the pharmaceutical formulation is administered daily forat least 1 month.

Methods for increasing secretion of meibum described herein may benefitfrom alternating administration of a two or more pharmaceuticalformulations described herein. Thus, in some embodiments, a method forincreasing secretion of meibum in a subject in need thereof, comprisesalternating administration of a first pharmaceutical formulation and asecond pharmaceutical formulation to the eyelids. In some embodiments,the first pharmaceutical formulation comprises a sub-antibiotic dose ofazithromycin and is applied daily and the second pharmaceuticalformulation comprises a sub-antiparasitic dose of an avermectin and isapplied daily. In some embodiments, the first pharmaceutical formulationcomprises a sub-antibiotic dose of azithromycin and is applied daily andthe second pharmaceutical formulation comprises a sub-antiparasitic doseof a dicarboxylic acid (e.g., azelaic acid) and is applied daily. Insome embodiments, the first pharmaceutical formulation comprises asub-antiparasitic dose of ivermectin and is applied daily and the secondpharmaceutical formulation comprises a sub-antiparasitic dose of adicarboxylic acid (e.g., azelaic acid) and is applied daily.Administration of the two pharmaceutical formulations may be alternateddaily, weekly, monthly, or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12months. In some embodiments, the alternating administration comprisesalternating the first and second pharmaceutical formulations daily. Insome embodiments, the alternating administration comprises alternatingthe first and second pharmaceutical formulations monthly. In someembodiments, the alternating administration comprises alternating thefirst and second pharmaceutical formulations every two months.

In some embodiments, the antibiotic applied in a sub-antibiotic dose toincrease secretion of meibum may be azithromycin. In some embodiments,provided herein is a method for increasing secretion of meibum in asubject in need thereof. In some embodiments, provided herein is amethod for increasing secretion of meibum in a subject in need thereof,comprising administering to the subject a pharmaceutical formulationcomprising a sub-antibiotic dose of azithromycin. In some embodiments,provided herein is a method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin, wherein; (a) the pharmaceutical formulation isadministered to the eyelid, and (b) the pharmaceutical formulation isadministered daily for at least 1 month. Methods for increasingsecretion of meibum in a subject in need thereof may compriseadministering a pharmaceutical formulation comprising a sub-antibioticdose of an azithromycin, further comprising a dicarboxylic acid (e.g.,azelaic acid).

Alternatively, the antiparasitic applied in a sub-antiparasitic dose toincrease production of meibum may be an avermectin. In some embodiments,provided herein is a method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin. In some embodiments, provided herein is a method forincreasing secretion of meibum in a subject in need thereof, comprisingadministering to the subject a pharmaceutical formulation comprising asub-antiparasitic dose of an avermectin, wherein; (a) the pharmaceuticalformulation is administered to the eyelid, and (b) the pharmaceuticalformulation is administered daily for at least 1 month. Methods forincreasing secretion of meibum in a subject in need thereof may compriseadministering a pharmaceutical formulation comprising asub-antiparasitic dose of an avermectin, further comprising adicarboxylic acid (e.g., azelaic acid). In some embodiments, theavermectin is ivermectin.

The mechanisms of action of the formulations and methods describedherein, as discussed above, are premised upon different mechanisms ofaction than are typically intended with use of the chemical agents(i.e., to treat bacterial or parasitic infection, to treatinflammation). Subjects who would benefit from the disclosedformulations and methods might not have a bacterial infection of theeye. In some embodiments, the subject in need thereof does not have aparasitic infection of the eye. In some embodiments, the subject in needthereof does not have a bacterial infection of the eye and does not havea parasitic infection of the eye. In some embodiments, the subject inneed thereof does not have a clinically diagnosable parasitic infectionof the eye. In some embodiments, the subject in need thereof does nothave a clinically diagnosable parasitic infection of the eye. In thiscontext, “clinically diagnosable” means the parasitic or bacterialinfection results in symptoms of infection, and is differentiated fromasymptomatic surface colonization.

Because the pharmaceutical formulations described herein increase thequality or quantity of meibum, they may be useful in enhancing thesafety or efficacy of existing treatments (e.g., expression, at-home hotcompresses, in-office energy-based devices), or addressing thedeficiencies thereof. In some embodiments, provided herein is a methodof enhancing the safety and efficacy of currently available DEDtreatments. In some embodiments, provided herein is a method ofenhancing the safety and efficacy of currently available MGD treatments.In some embodiments, the pharmaceutical formulations described hereinmay be used prior to using existing treatments for dry eye disease. Insome embodiments, provided herein are methods of using existingtreatments (e.g., heat-based therapies) in combination with the methodsand formulations described herein. For example, existing treatments maybe used before, concurrently with, or after any of the methods disclosedherein.

The pharmaceutical formulations of any of the methods described hereinmay be administered to the eyelid. In some embodiments, thepharmaceutical formulation is administered directly to the outer (e.g.,external) surface of the eyelid (e.g., external skin of the eyelid,above the lid margin, above the upper lashes, below the lower lashes).In some embodiments, the pharmaceutical formulation is administered tothe skin of the eyelid and not to the eyelid margin. In certainembodiments, the formulation may penetrate the skin of the eyelid and bedelivered to one or more meibomian glands. In certain embodiments, thepharmaceutical formulation is administered directly to the eyelidmargin. In certain embodiments, the pharmaceutical formulation isadministered to the eyelid indirectly. In certain embodiments, thepharmaceutical formulation is administered to the eyelid indirectly,having been applied to the ocular surface, making contact with the innersurface of the eyelid. In certain embodiments, the pharmaceuticalformulation is administered to the eyelid indirectly, having beenapplied to the ocular surface, making contact with the eyelid margin. Insome embodiments, the pharmaceutical formulation is administered to theeyelid via an ocular insert.

Application of the pharmaceutical formulation of the methods disclosedherein could be achieved via administration by any route suitable fordelivery to the eye. For instance, it may be useful to apply thepharmaceutical formulation via a dropper. In some embodiments, theformulation may be applied via an applicator stick. In some embodiments,the formulation may be applied by the finger. In some embodiments, theformulation may be applied via an ocular insert. In some embodiments,the pharmaceutical formulation may be rolled on or sprayed on.

As described above, the methods and formulations described herein may besuitable for treating one or more condition of the eye, whereinimprovement is observed in one or more symptoms of the condition of theeye. This improvement may be quantified in a number of ways. Forinstance, the methods and formulations described herein may result inreduced matrix metalloproteinase (e.g., MMP 9) activity in tears orsecretions. In some embodiments, matrix metalloproteinase activity maydecrease by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%). Incertain embodiments, the methods and formulations described herein mayresult in more liquified meibum, as quantified by an increased meibomiangland secretion score. In some embodiments, the meibomian glandsecretion score may increase by at least 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 100%, 200%, 300%, or 400%. In certain embodiments,the methods and formulations described herein may result in increasedlipid layer thickness, as measured by, for example, lipid layerinterferometry. In some embodiments, the lipid layer thickness mayincrease by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,100%, or 200%. In certain embodiments, the methods and formulationsdescribed herein may result in increased tear breakup times (TBUT). Insome embodiments, TBUT may increase by at least 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, or 400%. In certainembodiments, the methods and formulations described herein may result infewer symptoms reported by patients in subjective questionnaires (e.g.,Standard Patient Evaluation of Eye Dryness (SPEED); Ocular SurfaceDisease Index (OSDI), Symptom Assessment Questionnaire in Dry Eye(SANDE)). For instance, the methods and formulations may reduce SPEEDsymptoms, reduce OSDI symptoms, reduce SANDE symptoms, and/or reduce EyeDryness Score symptoms. In some embodiments, symptoms may be reduced byat least 5%, 10%, 20%, 30%, 40%, or 50%. In certain embodiments, themethods and formulations described herein may result in reduced injuryto the ocular surface, as evaluated by corneal and conjunctivalstaining. For instance, the methods and formulations described hereinmay result in decreased corneal and/or conjunctival staining. In someembodiments, staining may decrease by at least 5%, 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, or 100%. In certain embodiments, the methodsand formulations described herein may result in a decrease in the numberof obstructed, capped, and/or keratinized meibomian glands. In someembodiments, the number of obstructed, capped, and/or keratinizedmeibomian glands may decrease by at least 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, or 100%. In some embodiments, the methods andformulations described herein may result in reduced tear osmolarity. Insome embodiments, tear osmolarity may be reduced by at least 5%, 10%,20%, 30%, 40%, or 50%. In some embodiments, the methods and formulationsdescribed herein may result in reduced demodex mite counts.

The methods and formulations described herein may result in visionenhancement. In some embodiments, the methods and formulations describedherein may result in contact lens wear improvement (e.g., less wear). Incertain embodiments, the methods and formulations described herein mayresult in reading speed enhancement. In some embodiments, the methodsand formulations described herein may improve cataract surgery outcomesby improving the accuracy of pre-op measurements due to an improvementin tear film quality.

In some embodiments of the methods and formulations described herein, animprovement may be observed in one or more of the aforementionedsymptoms of the condition of the eye as measured over the course of, orafter, between about 1 week and about 1 year or greater after beginningapplication of a formulation. In some embodiments, the improvement maybe observed after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. Incertain embodiments, the improvement may be observed after 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,or 24 months. In some embodiments, the improvement may be observedbetween 1 and 24, between 1 and 18, between 1 and 12, between 1 and 6,between 1 and 2, between 2 and 4, between 2 and 6, between 2 and 12,between 2 and 18, between 2 and 24, between 3 and 24, between 3 and 18,between 3 and 12, between 6 and 24, between 6 and 18, between 6 and 12,between 12 and 24, between 12 and 18, or between 18 and 24 months.

Kits

In some embodiments, this disclosure also provides a pharmaceuticalpackage or kit comprising one or more containers filled with at leastone pharmaceutical formulation of this disclosure. Optionally associatedwith such a contains(s) can be an applicator for the formulation. Theapplicator could, for instance, be a dropper, applicator stick, orocular insert. Further associated with such a container(s) canoptionally be a notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, which notice reflects (a) approval by the agency ofmanufacture, use or sale for human administration, (b) directions foruse, or both. Instructions for use may also be provided.

In some embodiments, a pharmaceutical package or kit may include a heattherapy device (e.g., TearCare®).

The foregoing applies to any of the pharmaceutical formulations,methods, and uses described herein. This disclosure specificallycontemplates any combination of the features of such pharmaceuticalformulations, methods, and uses (alone or in combination) with thefeatures described for the various kits described in this section.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present disclosure,illustrative methods and materials are described herein. Other features,objects, and advantages of the disclosure will be apparent from thedescription and from the claims. In the specification and the appendedclaims, the singular forms also include the plural unless the contextclearly dictates otherwise. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs.

Each embodiment described herein may be taken alone or in combinationwith any one or more other embodiments.

Exemplary Embodiments

Embodiment I-1. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-2. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-3. A method for increasing secretion of meibum in a subjectin need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-4. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-5. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-6. A method for increasing secretion of meibum in a subjectin need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment I-7. The method of any one of embodiments I-4 to I-6, whereinthe avermectin is ivermectin.

Embodiment I-8. The method of any one of embodiments I-1 to I-7, whereinthe subject in need thereof does not have a bacterial infection of theeye.

Embodiment I-9. The method of any one of embodiments I-1 to I-7, whereinthe subject in need thereof does not have a parasitic infection of theeye.

Embodiment I-10. The method of any one of embodiments I-1 to I-3 or I-8to I-9, wherein the pharmaceutical formulation further comprises anavermectin.

Embodiment I-11. The method of any one of embodiments I-4 to I-10,wherein the pharmaceutical formulation further comprises azithromycin.

Embodiment I-12. The method of any one of embodiments I-1 to I-11wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment I-13. The method of any one of embodiments I-1 to I-12,wherein the pharmaceutical formulation further comprises animmunosuppressant.

Embodiment I-14. The method of embodiment 1-13, wherein theimmunosuppressant is selected from the group consisting of cyclosporine,tacrolimus, and lifitegrast.

Embodiment I-15. The method of any one of embodiments I-1 to I-3, I-8 toI-10, or I-12 to I-14, wherein the pharmaceutical formulation comprisesless than 1% w/v azithromycin.

Embodiment I-16. The method of any one of embodiments I-1 to I-3, I-8 toI-10, or I-12 to I-14, wherein the pharmaceutical formulation comprises0.5% w/v or less azithromycin.

Embodiment I-17. The method of any one of embodiments I-1 to I-3, I-8 toI-10, or I-12 to I-14, wherein the pharmaceutical formulation comprises0.1% w/v or less azithromycin.

Embodiment I-18. The method of any one of embodiments I-1 to I-3, I-8 toI-10, or I-12 to I-14, wherein the pharmaceutical formulation comprises0.01% w/v or less azithromycin.

Embodiment I-19. The method of any one of embodiments I-4 to I-9 or I-11to I-14, wherein the pharmaceutical formulation comprises less than 1%w/v of an avermectin.

Embodiment I-20. The method of any one of embodiments I-4 to I-9 or I-11to I-14, wherein the pharmaceutical formulation comprises 0.5% w/v orless of an avermectin.

Embodiment I-21. The method of any one of embodiments I-4 to I-9 or I-11to I-14, wherein the pharmaceutical formulation comprises 0.1% w/v orless of an avermectin.

Embodiment I-22. The method of any one of embodiments I-4 to I-9 or I-11to I-14, wherein the pharmaceutical formulation comprises 0.01% w/v orless of an avermectin.

Embodiment I-23. The method of any one of embodiments I-1 to I-22,wherein the pharmaceutical formulation is administered daily for 2months.

Embodiment I-24. The method of any one of embodiments I-1 to I-22,wherein the pharmaceutical formulation is administered daily for 6months.

Embodiment I-25. The method of any one of embodiments I-1 to I-10,wherein the pharmaceutical formulation is applied daily for at least 1year.

Embodiment I-26. The method of any one of embodiments I-1 to I-25,wherein the pharmaceutical formulation is applied as a cream, gelsuspension, solution, ointment, or spray.

Embodiment I-27. The method of any one of embodiments I-1 to I-25,wherein the pharmaceutical formulation is applied as drops.

Embodiment I-28. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin.

Embodiment I-29. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antiparasitic dose of an avermectin.

Embodiment I-30. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin and asub-antiparasitic dose of an avermectin.

Embodiment I-31. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising animmunosuppressant.

Embodiment II-1. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-2. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-3. A method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-4. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-5. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-6. A method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-7. The method of any one of embodiments II-4 to II-6,wherein the avermectin is ivermectin.

Embodiment II-8. The method of any one of embodiments II-1 to II-7,wherein the subject in need thereof does not have a bacterial infectionof the eye.

Embodiment II-9. The method of any one of embodiments II-1 to II-7,wherein the subject in need thereof does not have a parasitic infectionof the eye.

Embodiment II-10. The method of any one of embodiments II-1 to II-3 orII-8 to II-9, wherein the pharmaceutical formulation further comprisesan avermectin.

Embodiment II-11. The method of any one of embodiments II-4 to II-10,wherein the pharmaceutical formulation further comprises azithromycin.

Embodiment II-12. The method of any one of embodiments II-1 to II-11wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment II-13. The method of any one of embodiments II-1 to II-12,wherein the pharmaceutical formulation further comprises animmunosuppressant.

Embodiment II-14. The method of embodiment II-13, wherein theimmunosuppressant is selected from the group consisting of cyclosporine,tacrolimus, and lifitegrast.

Embodiment II-15. The method of any one of embodiments II-1 to II-3,II-8 to II-10, or II-12 to II-14, wherein the pharmaceutical formulationcomprises less than 1% w/v azithromycin.

Embodiment II-16. The method of any one of embodiments II-1 to II-3,II-8 to II-10, or II-12 to II-14, wherein the pharmaceutical formulationcomprises 0.5% w/v or less azithromycin.

Embodiment II-17. The method of any one of embodiments II-1 to II-3,II-8 to II-10, or II-12 to II-14, wherein the pharmaceutical formulationcomprises 0.1% w/v or less azithromycin.

Embodiment II-18. The method of any one of embodiments II-1 to II-3,II-8 to II-10, or II-12 to II-14, wherein the pharmaceutical formulationcomprises 0.01% w/v or less azithromycin.

Embodiment II-19. The method of any one of embodiments II-4 to II-9 orII-11 to II-14, wherein the pharmaceutical formulation comprises lessthan 1% w/v of an avermectin.

Embodiment II-20. The method of any one of embodiments II-4 to II-9 orII-11 to II-14, wherein the pharmaceutical formulation comprises 0.5%w/v or less of an avermectin.

Embodiment II-21. The method of any one of embodiments II-4 to II-9 orII-11 to II-14, wherein the pharmaceutical formulation comprises 0.1%w/v or less of an avermectin.

Embodiment II-22. The method of any one of embodiments II-4 to II-9 orII-11 to II-14, wherein the pharmaceutical formulation comprises 0.01%w/v or less of an avermectin.

Embodiment II-23. The method of any one of embodiments II-1 to II-22,wherein the pharmaceutical formulation is administered daily for 2months.

Embodiment II-24. The method of any one of embodiments II-1 to II-22,wherein the pharmaceutical formulation is administered daily for 6months.

Embodiment II-25. The method of any one of embodiments II-1 to II-10,wherein the pharmaceutical formulation is applied daily for at least 1year.

Embodiment II-26. The method of any one of embodiments II-1 to II-25,wherein the pharmaceutical formulation is applied as a cream, gel,suspension, solution, ointment, or spray.

Embodiment II-27. The method of any one of embodiments II-1 to II-25,wherein the pharmaceutical formulation is applied as drops.

Embodiment II-28. The method of any one of embodiments II-1 to II-27,wherein the pharmaceutical formulation further comprises azelaic acid.

Embodiment II-29. The method of embodiment II-28, wherein theconcentration of azelaic acid is between about 1% and about 20%.

Embodiment II-30. The method of embodiments II-28 to II-29, wherein theconcentration of azelaic acid is between about 10% and about 15%.

Embodiment II-31. The method of any one of embodiments II-28 to II-30,wherein the pharmaceutical formulation comprises between about 10% andabout 20% azelaic acid and about 0.4% to about 0.5% azithromycin.

Embodiment II-32. The method of any one of embodiments II-1 to II-31further comprising at least one of mineral oil, petrolatum, propyleneglycol, and polyethylene glycol.

Embodiment II-33. A method for treating dry eye disease in a subject inneed thereof, comprising alternating administration of a firstpharmaceutical formulation and a second pharmaceutical formulation tothe eyelid, wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is applied daily, and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is applied daily.

Embodiment II-34. A method for treating blepharitis in a subject in needthereof, comprising alternating administration of a first pharmaceuticalformulation and a second pharmaceutical formulation to the eyelid,wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is applied daily, and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is applied daily.

Embodiment II-35. A method for increasing secretion of meibum in asubject in need thereof, comprising alternating administration of afirst pharmaceutical formulation and a second pharmaceutical formulationto the eyelids, wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is applied daily, and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is applied daily.

Embodiment II-36. The method of any one of embodiments II-33 to II-35,wherein the alternating administration comprises alternating the firstand second pharmaceutical formulations daily.

Embodiment II-37. The method of any one of embodiments II-33 to II-35,wherein the alternating administration comprises alternating the firstand second pharmaceutical formulations monthly.

Embodiment II-38. The method of any one of embodiments II-33 to II-35,wherein the alternating administration comprises alternating the firstand second pharmaceutical formulation every two months.

Embodiment II-39. The method of any one of embodiments II-33 to II-38,wherein the avermectin is ivermectin.

Embodiment II-40. The method of any one of embodiments II-33 to II-39,wherein the subject in need thereof does not have a bacterial infectionof the eye.

Embodiment II-41. The method of any one of embodiments II-33 to II-40,wherein the subject in need thereof does not have a parasitic infectionof the eye.

Embodiment II-42. The method of any one of embodiments II-33 to II-41,wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment II-43. The method of any one of embodiments II-33 to II-42,wherein the pharmaceutical formulation further comprises animmunosuppressant.

Embodiment II-44. The method of embodiment II-43 wherein theimmunosuppressant is selected from the group consisting of cyclosporine,tacrolimus, and lifitegrast.

Embodiment II-45. The method of any one of embodiments II-33 to II-44,wherein the first pharmaceutical formulation comprises less than 1% w/vazithromycin.

Embodiment II-46. The method of any one of embodiments II-33 to II-45,wherein the first pharmaceutical formulation comprises 0.5% w/v or lessazithromycin.

Embodiment II-47. The method of any one of embodiments II-33 to II-46,wherein the first pharmaceutical formulation comprises 0.1% w/v or lessazithromycin.

Embodiment II-48. The method of any one of embodiments II-33 to II-47,wherein the first pharmaceutical formulation comprises 0.01% w/v or lessazithromycin.

Embodiment II-49. The method of any one of embodiments II-33 to II-48,wherein the second pharmaceutical formulation comprises less than 1% w/vof an avermectin.

Embodiment II-50. The method of any one of embodiments II-33 to II-49,wherein the second pharmaceutical formulation comprises 0.5% w/v or lessof an avermectin.

Embodiment II-51. The method of any one of embodiments II-33 to II-50,wherein the second pharmaceutical formulation comprises 0.1% w/v or lessof an avermectin.

Embodiment II-52. The method of any one of embodiments II-33 to II-51,wherein the second pharmaceutical formulation comprises 0.01% w/v orless of an avermectin.

Embodiment II-53. The method of any one of embodiments II-33 to II-52,wherein each of the first pharmaceutical formulation and the secondpharmaceutical formulations is applied as one of a cream, gel,suspension, solution, ointment, or spray.

Embodiment II-54. The method of any one of embodiments II-33 to II-52,wherein the first pharmaceutical formulation and the secondpharmaceutical formulation are applied as drops.

Embodiment II-55. A method of treating dry eye disease or blepharitis ina subject in need thereof, comprising administering to the subject apharmaceutical formulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-56. A method of treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-57. A method of increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment II-58. The method of any one of embodiments II-55 to II-57,wherein the pharmaceutical formulation is administered once daily.

Embodiment II-59. The method of any one of embodiments II-55 to II-57,wherein the pharmaceutical formulation is administered twice daily.

Embodiment II-60. The method of any one of embodiments II-55 to II-59,wherein the concentration of azelaic acid is between about 1% and about20%.

Embodiment II-61. The method of any one of embodiments II-55 to II-60,wherein the concentration of azelaic acid is between about 10% and about15%.

Embodiment II-62. The method of any one of embodiments II-55 to II-61wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment II-63. The method of any one of embodiments II-55 to II-62,wherein the pharmaceutical formulation is administered daily for atleast 2 months.

Embodiment II-64. The method of any one of embodiments II-55 to II-63,wherein the pharmaceutical formulation is administered daily for atleast 6 months.

Embodiment II-65. The method of any one of embodiments II-55 to II-64,wherein the pharmaceutical formulation is administered daily for atleast 1 year.

Embodiment II-66. The method of any one of embodiments II-55 to II-65,wherein the pharmaceutical formulation is applied as a cream, gel,suspension, solution, ointment, or spray.

Embodiment II-67. The method of any one of embodiments II-55 to II-65,wherein the pharmaceutical formulation is applied as drops.

Embodiment II-68. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin.

Embodiment II-69. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antiparasitic dose of an avermectin.

Embodiment II-70. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin and asub-antiparasitic dose of an avermectin.

Embodiment II-71. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising animmunosuppressant.

Embodiment II-72. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising azelaicacid.

Embodiment II-73. The pharmaceutical formulation of embodiment II-72,comprising between about 0.4% and 0.5% azithromycin and between about10% and 15% azelaic acid.

Embodiment II-74. A pharmaceutical formulation for treating a conditionof the eye, comprising azelaic acid.

Embodiment II-75. The pharmaceutical formulation of embodiment II-74comprising between about 10% and 15% azelaic acid.

Embodiment II-76. A method for treating dry eye disease, treatingblepharitis, or increasing secretion of meibum in a subject in needthereof, comprising administering to the eyelid of the subject apharmaceutical formulation comprising:

-   -   a) between about 5% and about 15% azelaic acid, and    -   b) between about 0.4% to about 0.5% azithromycin;

wherein, the pharmaceutical formulation is administered daily for atleast 1 month.

Embodiment II-77. The method of any one of embodiment II-2, II-5, II-34,II-55 or II-76, wherein the blepharitis is caused by demodex mites.

Embodiment II-78. The method of embodiment II-76, wherein the azelaicacid addresses anterior blepharitis and the azithromycin addressesposterior blepharitis.

Embodiment II-79. The pharmaceutical formulation of embodiment II-74 orII-75, wherein the azelaic acid addresses anterior blepharitis.

Embodiment II-80. A method for treating a condition of the eyecomprising administering to the subject a pharmaceutical formulationcomprising:

-   -   a) a sub-antibiotic dose of azithromycin;    -   b) a sub-antiparasitic dose of an avermectin;    -   c) a sub-antibiotic dose of azithromycin and a sub-antiparasitic        dose of an avermectin;    -   d) a sub-antibiotic dose of azithromycin or a sub-antiparasitic        dose of an avermectin, and further comprising an        immunosuppressant;    -   e) a sub-antibiotic dose of azithromycin or a sub-antiparasitic        dose of an avermectin, and further comprising azelaic acid; or    -   f) azelaic acid;        wherein the pharmaceutical formulation is applied to the eyelid        daily for at least 1 month.

Embodiment II-81. The method of embodiment II-80, wherein the conditionof the eye is one or more of dry eye disease, blepharitis, and meibomiangland dysfunction.

Embodiment II-82. The pharmaceutical formulation of any one ofembodiments II-68 to II-75, wherein the condition of the eye is one ormore of dry eye disease, blepharitis, and meibomian gland dysfunction.

Embodiment III-1. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-2. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antibiotic dose of azithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-3. A method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antibiotic dose ofazithromycin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-4. A method for treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-5. A method for treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising a sub-antiparasitic dose of an avermectin,wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-6. A method for increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising a sub-antiparasitic dose of anavermectin, wherein

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-7. The method of any one of embodiments III-4 to III-6,wherein the avermectin is ivermectin.

Embodiment III-8. The method of any one of embodiments III-1 to III-7,wherein the subject in need thereof does not have a bacterial infectionof the eye.

Embodiment III-9. The method of any one of embodiments III-1 to III-7,wherein the subject in need thereof does not have a parasitic infectionof the eye.

Embodiment III-10. The method of any one of embodiments III-1 to III-3or III-8 to III-9, wherein the pharmaceutical formulation furthercomprises an avermectin.

Embodiment III-11. The method of any one of embodiments III-4 to III-10,wherein the pharmaceutical formulation further comprises azithromycin.

Embodiment III-12. The method of any one of embodiments III-1 to III-11wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment III-13. The method of any one of embodiments III-1 to III-12,wherein the pharmaceutical formulation further comprises animmunosuppressant.

Embodiment III-14. The method of embodiment III-13, wherein theimmunosuppressant is selected from the group consisting of cyclosporine,tacrolimus, and lifitegrast.

Embodiment III-15. The method of any one of embodiments III-1 to III-3,III-8 to III-10, or III-12 to III-14, wherein the pharmaceuticalformulation comprises less than 1% w/v azithromycin.

Embodiment III-16. The method of any one of embodiments III-1 to III-3,III-8 to III-10, or III-12 to III-14, wherein the pharmaceuticalformulation comprises 0.5% w/v or less azithromycin.

Embodiment III-17. The method of any one of embodiments III-1 to III-3,III-8 to III-10, or III-12 to III-14, wherein the pharmaceuticalformulation comprises 0.1% w/v or less azithromycin.

Embodiment III-18. The method of any one of embodiments III-1 to III-3,III-8 to III-10, or III-12 to III-14, wherein the pharmaceuticalformulation comprises 0.01% w/v or less azithromycin.

Embodiment III-19. The method of any one of embodiments III-4 to III-9or III-11 to III-14, wherein the pharmaceutical formulation comprisesless than 1% w/v of an avermectin.

Embodiment III-20. The method of any one of embodiments III-4 to III-9or III-11 to III-14, wherein the pharmaceutical formulation comprises0.5% w/v or less of an avermectin.

Embodiment III-21. The method of any one of embodiments III-4 to III-9or III-11 to III-14, wherein the pharmaceutical formulation comprises0.1% w/v or less of an avermectin.

Embodiment III-22. The method of any one of embodiments III-4 to III-9or III-11 to III-14, wherein the pharmaceutical formulation comprises0.01% w/v or less of an avermectin.

Embodiment III-23. The method of any one of embodiments III-1 to III-22,wherein the pharmaceutical formulation is administered daily for 2months.

Embodiment III-24. The method of any one of embodiments III-1 to III-22,wherein the pharmaceutical formulation is administered daily for 6months.

Embodiment III-25. The method of any one of embodiments III-1 to III-10,wherein the pharmaceutical formulation is administered daily for atleast 1 year.

Embodiment III-26. The method of any one of embodiments III-1 to III-25,wherein the pharmaceutical formulation is administered as a cream, gel,suspension, solution, ointment, or spray.

Embodiment III-27. The method of any one of embodiments III-1 to III-25,wherein the pharmaceutical formulation is administered as drops.

Embodiment III-28. The method of any one of embodiments III-1 to III-27,wherein the pharmaceutical formulation further comprises azelaic acid.

Embodiment III-29. The method of embodiment III-28, wherein theconcentration of azelaic acid is between about 1% and about 20%.

Embodiment III-30. The method of embodiments III-28 to III-29, whereinthe concentration of azelaic acid is between about 10% and about 15%.

Embodiment III-31. The method of any one of embodiments III-28 toIII-30, wherein the pharmaceutical formulation comprises between about10% and about 20% azelaic acid and about 0.4% to about 0.5%azithromycin.

Embodiment III-32. The method of any one of embodiments III-1 to III-31further comprising at least one of mineral oil, petrolatum, propyleneglycol, and polyethylene glycol.

Embodiment III-33. A method for treating dry eye disease in a subject inneed thereof, comprising alternating administration of a firstpharmaceutical formulation and a second pharmaceutical formulation tothe eyelid, wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is administered daily,        and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is administered        daily.

Embodiment III-34. A method for treating blepharitis in a subject inneed thereof, comprising alternating administration of a firstpharmaceutical formulation and a second pharmaceutical formulation tothe eyelid, wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is administered daily,        and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is administered        daily.

Embodiment III-35. A method for increasing secretion of meibum in asubject in need thereof, comprising alternating administration of afirst pharmaceutical formulation and a second pharmaceutical formulationto the eyelids, wherein

-   -   a) the first pharmaceutical formulation comprises a        sub-antibiotic dose of azithromycin and is administered daily,        and    -   b) the second pharmaceutical formulation comprises a        sub-antiparasitic dose of an avermectin and is administered        daily.

Embodiment III-36. The method of any one of embodiments III-33 toIII-35, wherein the alternating administration comprises alternating thefirst and second pharmaceutical formulations daily.

Embodiment III-37. The method of any one of embodiments III-33 toIII-35, wherein the alternating administration comprises alternating thefirst and second pharmaceutical formulations monthly.

Embodiment III-38. The method of any one of embodiments III-33 toIII-35, wherein the alternating administration comprises alternating thefirst and second pharmaceutical formulation every two months.

Embodiment III-39. The method of any one of embodiments III-33 toIII-38, wherein the avermectin is ivermectin.

Embodiment III-40. The method of any one of embodiments III-33 toIII-39, wherein the subject in need thereof does not have a bacterialinfection of the eye.

Embodiment III-41. The method of any one of embodiments III-33 toIII-40, wherein the subject in need thereof does not have a parasiticinfection of the eye.

Embodiment III-42. The method of any one of embodiments III-33 toIII-41, wherein the pharmaceutical formulation further comprises atleast one skin penetration enhancer.

Embodiment III-43. The method of any one of embodiments III-33 toIII-42, wherein the pharmaceutical formulation further comprises animmunosuppressant.

Embodiment III-44. The method of embodiment III-43 wherein theimmunosuppressant is selected from the group consisting of cyclosporine,tacrolimus, and lifitegrast.

Embodiment III-45. The method of any one of embodiments III-33 toIII-44, wherein the first pharmaceutical formulation comprises less than1% w/v azithromycin.

Embodiment III-46. The method of any one of embodiments III-33 toIII-45, wherein the first pharmaceutical formulation comprises 0.5% w/vor less azithromycin.

Embodiment III-47. The method of any one of embodiments III-33 toIII-46, wherein the first pharmaceutical formulation comprises 0.1% w/vor less azithromycin.

Embodiment III-48. The method of any one of embodiments III-33 toIII-47, wherein the first pharmaceutical formulation comprises 0.01% w/vor less azithromycin.

Embodiment III-49. The method of any one of embodiments III-33 toIII-48, wherein the second pharmaceutical formulation comprises lessthan 1% w/v of an avermectin.

Embodiment III-50. The method of any one of embodiments III-33 toIII-49, wherein the second pharmaceutical formulation comprises 0.5% w/vor less of an avermectin.

Embodiment III-51. The method of any one of embodiments III-33 toIII-50, wherein the second pharmaceutical formulation comprises 0.1% w/vor less of an avermectin.

Embodiment III-52. The method of any one of embodiments III-33 toIII-51, wherein the second pharmaceutical formulation comprises 0.01%w/v or less of an avermectin.

Embodiment III-53. The method of any one of embodiments III-33 toIII-52, wherein each of the first pharmaceutical formulation and thesecond pharmaceutical formulations is administered as one of a cream,gel, suspension, solution, ointment, or spray.

Embodiment III-54. The method of any one of embodiments III-33 toIII-52, wherein the first pharmaceutical formulation and the secondpharmaceutical formulation are administered as drops.

Embodiment III-55. A method of treating dry eye disease in a subject inneed thereof, comprising administering to the subject a pharmaceuticalformulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-56. A method of treating blepharitis in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-57. A method of increasing secretion of meibum in asubject in need thereof, comprising administering to the subject apharmaceutical formulation comprising azelaic acid, wherein:

-   -   a) the pharmaceutical formulation is administered to the eyelid,        and    -   b) the pharmaceutical formulation is administered daily for at        least 1 month.

Embodiment III-58. The method of any one of embodiments III-55 toIII-57, wherein the pharmaceutical formulation is administered oncedaily.

Embodiment III-59. The method of any one of embodiments III-55 toIII-57, wherein the pharmaceutical formulation is administered twicedaily.

Embodiment III-60. The method of any one of embodiments III-55 toIII-59, wherein the concentration of azelaic acid is between about 1%and about 20%.

Embodiment III-61. The method of any one of embodiments III-55 toIII-60, wherein the concentration of azelaic acid is between about 10%and about 15%.

Embodiment III-62. The method of any one of embodiments III-55 to III-61wherein the pharmaceutical formulation further comprises at least oneskin penetration enhancer.

Embodiment III-63. The method of any one of embodiments III-55 toIII-62, wherein the pharmaceutical formulation is administered daily forat least 2 months.

Embodiment III-64. The method of any one of embodiments III-55 toIII-63, wherein the pharmaceutical formulation is administered daily forat least 6 months.

Embodiment III-65. The method of any one of embodiments III-55 toIII-64, wherein the pharmaceutical formulation is administered daily forat least 1 year.

Embodiment III-66. The method of any one of embodiments III-55 toIII-65, wherein the pharmaceutical formulation is administered as acream, gel, suspension, solution, ointment, or spray.

Embodiment III-67. The method of any one of embodiments III-55 toIII-65, wherein the pharmaceutical formulation is administered as drops.

Embodiment III-68. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin.

Embodiment III-69. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antiparasitic dose of an avermectin.

Embodiment III-70. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin and asub-antiparasitic dose of an avermectin.

Embodiment III-71. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising animmunosuppressant.

Embodiment III-72. A pharmaceutical formulation for treating a conditionof the eye, comprising a sub-antibiotic dose of azithromycin or asub-antiparasitic dose of an avermectin, and further comprising azelaicacid.

Embodiment III-73. The pharmaceutical formulation of embodiment III-72,comprising between about 0.4% and 0.5% azithromycin and between about10% and 15% azelaic acid.

Embodiment III-74. A pharmaceutical formulation for treating a conditionof the eye, comprising azelaic acid.

Embodiment III-75. The pharmaceutical formulation of embodiment III-74comprising between about 10% and 15% azelaic acid.

Embodiment III-76. A method for treating dry eye disease, treatingblepharitis, or increasing secretion of meibum in a subject in needthereof, comprising administering to the eyelid of the subject apharmaceutical formulation comprising:

-   -   a) between about 5% and about 15% azelaic acid, and    -   b) between about 0.4% to about 0.5% azithromycin;

wherein, the pharmaceutical formulation is administered daily for atleast 1 month.

Embodiment III-77. The method of any one of embodiments III-2, III-5,III-34, III-55 or III-76, wherein the blepharitis is caused by demodexmites.

Embodiment III-78. The method of embodiment III-76, wherein the azelaicacid addresses anterior blepharitis and the azithromycin addressesposterior blepharitis.

Embodiment III-79. The pharmaceutical formulation of embodiment III-74or III-75, wherein the azelaic acid addresses anterior blepharitis.

Embodiment III-80. A method for treating a condition of the eyecomprising administering to the subject a pharmaceutical formulationcomprising:

-   -   a) a sub-antibiotic dose of azithromycin;    -   b) a sub-antiparasitic dose of an avermectin;    -   c) a sub-antibiotic dose of azithromycin and a sub-antiparasitic        dose of an avermectin;    -   d) a sub-antibiotic dose of azithromycin or a sub-antiparasitic        dose of an avermectin, and further comprising an        immunosuppressant;    -   e) a sub-antibiotic dose of azithromycin or a sub-antiparasitic        dose of an avermectin, and further comprising azelaic acid; or    -   f) azelaic acid;        wherein the pharmaceutical formulation is administered to the        eyelid daily for at least 1 month.

Embodiment III-81. The method of embodiment III-80, wherein thecondition of the eye is one or more of dry eye disease, blepharitis, andmeibomian gland dysfunction.

Embodiment III-82. The pharmaceutical formulation of any one ofembodiments III-68 to III-75, wherein the condition of the eye is one ormore of dry eye disease, blepharitis, and meibomian gland dysfunction.

Embodiment III-83. A method of treating dry eye disease comprisingadministering to an external surface of an eyelid of a subject apharmaceutical formulation comprising azelaic acid, wherein theadministration of said pharmaceutical formulation reduces a symptom ofdry eye disease.

Embodiment III-84. The method of embodiment III-83, wherein the dry eyedisease is tear deficient dry eye.

Embodiment III-85. The method of embodiment III-83, wherein the dry eyedisease is evaporative dry eye.

Embodiment III-86. The method of embodiment III-83, wherein the symptomof dry eye disease is meibomian gland dysfunction, redness, stinging,burning, itching, light sensitivity, watery eyes, blurry vision,irregularities of the ocular surface, or damage to corneal orconjunctival epithelium and tissues.

Embodiment III-87. The method of embodiment III-83, wherein theadministration of said pharmaceutical formulation further improves theamount or quality of meibum produced.

Embodiment III-88. The method of embodiment III-83, wherein the dry eyedisease does not result from infection or inflammation of tissue.

Embodiment III-89. The method of embodiments III-83, wherein thepharmaceutical formulation is administered daily.

Embodiment III-90. The method of embodiment III-83, wherein thepharmaceutical formulation is administered twice daily.

Embodiment III-91. The method of embodiment III-83, wherein thepharmaceutical formulation is administered daily for at least 6 months.

Embodiment III-92. The method of embodiment III-83, wherein thepharmaceutical formulation is administered daily for at least 1 year.

Embodiment III-93. The method of embodiment III-83, wherein thepharmaceutical formulation is administered as a cream, gel, suspension,solution, ointment, or spray.

Embodiment III-94. The method of embodiment III-93, wherein thepharmaceutical formulation is administered as a cream.

Embodiment III-95. The method of embodiment III-93, wherein thepharmaceutical formulation is administered as a gel.

Embodiment III-96. The method of embodiment III-83, wherein aconcentration of azelaic acid in the pharmaceutical formulation isbetween about 1% and about 20%.

Embodiment III-97. The method of embodiment III-96, wherein theconcentration of azelaic acid in the pharmaceutical formulation isbetween about 10% and about 15%.

Embodiment III-98. The method of embodiment III-83, wherein thepharmaceutical formulation further comprises azithromycin.

Embodiment III-99. The method of embodiment III-98, wherein aconcentration of azithromycin in the pharmaceutical formulation isbetween about 0.1% and 0.5%.

Embodiment III-100. The method of embodiment III-83, wherein thepharmaceutical formulation further comprises an avermectin.

Embodiment III-101. The method of embodiment III-98, wherein aconcentration of the avermectin in the pharmaceutical formulation isbetween about 0.1% and 0.5%.

Embodiment III-102. The method of embodiment III-100, wherein theavermectin is ivermectin.

Embodiment III-103. The method of embodiment III-83, wherein thepharmaceutical formulation further comprises at least one skinpenetration enhancer.

Embodiment III-104. A method of treating blepharitis comprisingadministering to an external surface of an eyelid of a subject apharmaceutical formulation comprising azelaic acid, wherein theadministration of said pharmaceutical formulation reduces a symptom ofblepharitis.

Embodiment III-105. The method of embodiment III-104, wherein theblepharitis is anterior blepharitis.

Embodiment III-106. The method of embodiment III-104, wherein theblepharitis is posterior blepharitis.

Embodiment III-107. The method of embodiment III-104, wherein thesymptom of blepharitis is irritation, reddening, itching, burning,edema, or crusting.

Embodiment III-108. The method of embodiment III-104, wherein theadministration of said pharmaceutical formulation further improves theamount or quality of meibum produced.

Embodiment III-109. The method of embodiment III-104, wherein theblepharitis does not result from bacterial or parasitic infection.

Embodiment III-110. The method of embodiment III-104, wherein thepharmaceutical formulation is administered daily.

Embodiment III-111. The method of embodiment III-104, wherein thepharmaceutical formulation is administered twice daily.

Embodiment III-112. The method of embodiment III-110, wherein thepharmaceutical formulation is administered daily for at least 6 months.

Embodiment III-113. The method of embodiment III-110, wherein thepharmaceutical formulation is administered daily for at least 1 year.

Embodiment III-114. The method of embodiment III-104, wherein thepharmaceutical formulation is administered as a cream, gel, suspension,solution, ointment, or spray.

Embodiment III-115. The method of embodiment III-114, wherein thepharmaceutical formulation is administered as a cream.

Embodiment III-116. The method of embodiment III-114, wherein thepharmaceutical formulation is administered as a gel.

Embodiment III-117. The method of embodiment III-104, wherein aconcentration of azelaic acid in the pharmaceutical formulation isbetween about 1% and about 20%.

Embodiment III-118. The method of embodiment III-117, wherein theconcentration of azelaic acid in the pharmaceutical formulation isbetween about 10% and about 15%.

Embodiment III-119. The method of embodiment III-104, wherein thepharmaceutical formulation further comprises azithromycin.

Embodiment III-120. The method of embodiment III-119, wherein aconcentration of azithromycin in the pharmaceutical formulation isbetween about 0.1% and 0.5%.

Embodiment III-121. The method of embodiment III-104, wherein thepharmaceutical formulation further comprises an avermectin.

Embodiment III-122. The method of embodiment III-121, wherein aconcentration of the avermectin in the pharmaceutical formulation isbetween about 0.1% and 0.5%.

Embodiment III-123. The method of embodiment III-104, wherein thepharmaceutical formulation further comprises at least one skinpenetration enhancer.

Embodiment III-124. A method for increasing secretion of meibumcomprising administering to an external surface of an eyelid of asubject a pharmaceutical formulation comprising azelaic acid, whereinthe administration of said pharmaceutical formulation reduces a symptomof inadequate tear production or poor quality of tears.

Embodiment III-125. The method of embodiment III-124, wherein meibumfluidity is increased.

Embodiment III-126. The method of embodiment III-124, wherein meibummelting temperature is lowered.

Embodiment III-126B. The method of embodiment III-124, wherein thesymptom of inadequate tear production or poor quality of tears isexcessive evaporation of water from the ocular surface.

Embodiment III-127. The method of embodiment III-124, wherein thesymptom of inadequate tear production or poor quality of tears isredness, stinging, burning, itching, light sensitivity, watery eyes,blurry vision, irregularities of the ocular surface, or damage tocorneal or conjunctival epithelium and tissues.

Embodiment III-128. The method of embodiment III-124, wherein thepharmaceutical formulation is administered daily.

Embodiment III-129. The method of embodiment III-124, wherein thepharmaceutical formulation is administered twice daily.

Embodiment III-130. The method of embodiment III-128, wherein thepharmaceutical formulation is administered daily for at least 6 months.

Embodiment III-131. The method of embodiment III-128, wherein thepharmaceutical formulation is administered daily for at least 1 year.

Embodiment III-132. The method of embodiment III-124, wherein thepharmaceutical formulation is administered as a cream, gel, suspension,solution, ointment, or spray.

Embodiment III-133. The method of embodiment III-132, wherein thepharmaceutical formulation is administered as a cream.

Embodiment III-134. The method of embodiment III-132, wherein thepharmaceutical formulation is administered as a gel.

Embodiment III-135. The method of embodiment III-124, wherein aconcentration of azelaic acid in the pharmaceutical formulation isbetween about 1% and about 20%.

Embodiment III-136. The method of embodiment III-135, wherein theconcentration of azelaic acid in the pharmaceutical formulation isbetween about 10% and about 15%.

Embodiment III-137. The method of embodiment III-124, wherein thepharmaceutical formulation further comprises azithromycin.

Embodiment III-138. The method of embodiment III-137, wherein aconcentration of azithromycin in the pharmaceutical formulation isbetween about 0.1% and 0.5%.

Embodiment III-139. The method of embodiment III-124, wherein thepharmaceutical formulation further comprises an avermectin.

Embodiment III-140. A method for treating dry eye disease, comprisingadministering to an external surface of an eyelid of a subject apharmaceutical formulation comprising:

-   -   a) between about 1% and about 20% azelaic acid; and    -   b) between about 0.1% and about 0.5% azithromycin,        wherein the pharmaceutical formulation is administered to the        external surface of the eyelid daily for at least 1 month, and        wherein administering the pharmaceutical formulation reduces a        symptom of dry eye disease.

Embodiment III-141. The method of embodiment III-140, wherein thesymptom of dry eye disease is meibomian gland dysfunction, redness,stinging, burning, itching, light sensitivity, watery eyes, blurryvision, irregularities of the ocular surface, or damage to corneal orconjunctival epithelium and tissues.

Embodiment III-142. The method of embodiment III-140, wherein the dryeye disease is aqueous tear-deficient dry eye (ADDE).

Embodiment III-143. The method of embodiment III-140, wherein the dryeye disease is evaporative dry eye (EDE).

Embodiment III-144. The method of embodiment III-140, wherein ADDE andEDE are treated simultaneously.

Embodiment III-145. The method of embodiment III-140, wherein theadministration of said pharmaceutical formulation further reduces asymptom of blepharitis.

Embodiment III-146. The method of embodiment III-145, wherein theblepharitis is anterior blepharitis.

Embodiment III-147. The method of embodiment III-145, wherein theblepharitis is posterior blepharitis.

Embodiment III-148. The method of embodiment III-145, wherein theblepharitis is both anterior blepharitis and posterior blepharitis.

Embodiment III-149. The method of embodiment III-140, wherein theadministration of said pharmaceutical formulation further improves theamount or quality of meibum produced.

Embodiment III-150. The method of embodiment III-140, wherein the dryeye disease does not result from bacterial infection, parasiticinfection, or inflammation of tissue.

Embodiment III-151. The method of embodiment III-140, wherein theconcentration of azelaic acid is between about 5% and 20%.

Embodiment III-152. The method of embodiment III-140, wherein theconcentration of azelaic acid is between about 5% and 15%.

Embodiment III-153. The method of embodiment III-140, wherein theconcentration of azelaic acid is between about 5% and 15% and theconcentration of azithromycin is between about 0.4% and about 0.5%.

Embodiment III-154. The method of embodiment III-140, wherein theconcentration of azelaic acid is about 10% and the concentration ofazithromycin is about 0.4%.

Embodiment III-155. The method of embodiment III-140, wherein thepharmaceutical formulation is administered twice daily.

Embodiment III-156. The method of embodiment III-140, wherein thepharmaceutical formulation is administered daily for at least 6 months.

Embodiment III-157. The method of embodiment III-140, wherein thepharmaceutical formulation is administered daily for at least 1 year.

Embodiment III-158. The method of embodiment III-140, wherein thepharmaceutical formulation is administered as a cream, gel, suspension,solution, ointment, or spray.

Embodiment III-159. The method of embodiment III-157, wherein thepharmaceutical formulation is administered as a cream.

Embodiment III-160. The method of embodiment III-157, wherein thepharmaceutical formulation is administered as a gel.

Embodiment III-161. The method of embodiment III-162, wherein thepharmaceutical formulation further comprises at least one skinpenetration enhancer.

Embodiment III-162. The method of any one of embodiments III-1 toIII-32, III-55 to III-67, III-76 to III-161, wherein the pharmaceuticalformulation further comprises at least one polyol.

Embodiment III-163. The method of any one of embodiments III-33 toIII-54, wherein the first pharmaceutical formulation and the secondpharmaceutical formulation each independently comprise at least onepolyol.

Embodiment III-164. The pharmaceutical formulation of any one ofembodiments III-68 to III-75, wherein the pharmaceutical formulationfurther comprises at least one polyol.

Embodiment III-165. The method of embodiment III-162 or III-163, whereinthe at least one polyol is selected from propylene glycol, polyethyleneglycol, glycerol, erythritol, mannitol, or sorbitol.

Embodiment III-166. The method of embodiment III-165, wherein the atleast one polyol is propylene glycol.

Embodiment III-167. A pharmaceutical formulation comprising betweenabout 1% and about 20% azelaic acid and between about 0.1% and about0.5% azithromycin.

Embodiment III-168. Use of the pharmaceutical formulation of any one ofembodiments III-68 to III-75, or III-167 in the manufacture of amedicament for treating a condition of the eye or for increasingsecretion of meibum.

Embodiment III-169. Use of the pharmaceutical formulation of any one ofembodiments III-68 to III-75, or III-167 as a medicament for treating acondition of the eye or for increasing secretion of meibum.

Embodiment III-170. Use of the pharmaceutical formulation of any one ofembodiments III-68 to III-75, or III-167 for treating a condition of theeye or for increasing secretion of meibum.

Embodiment III-171. The use of any one of embodiments III-168 to III-170wherein the condition of the eye is dry eye disease or blepharitis.

EXAMPLES Example 1: Human Clinical Trials for PharmaceuticalFormulations

Human subjects diagnosed with dry eye disease are assigned to arms fortreatment with one of four formulations: (1) azithromycin, (2) azelaicacid, (3) azithromycin and azelaic acid, or (4) vehicle only. Eachpatient is given a baseline exam of visual acuity, intraocular pressure,slit lamp exam, conjunctival and corneal staining, meibomian glandscoring, tear break up time, SPEED questionnaire, and subjective dry eyequestionnaires (SANDE).

Subjects are treated by nightly or twice daily with administration ofthe respective formulation for at least one month. Subjects are examinedat 1 week, 2 weeks, and 4 weeks. Trial endpoints are based on tear breakup time, meibomian gland scores, corneal and conjunctival staining(decreased is good, increased may indicate toxicity), andquestionnaires. Toxicity is detected by increased staining of cornea orconjunctiva. Patients may be assessed by one or more of matrixmetalloproteinase activity, meibomian gland secretion scoring, lipidlayer interferometry, tear break up time, subjective questionnaires(SPEED, OSDI, SANDE), corneal and conjunctival staining, meibomian glandobstructions, or tear osmolarity.

What is claimed is:
 1. A method for treating dry eye disease comprising:administering to an external surface of an upper eyelid above an upperlid margin a pharmaceutical formulation comprising: a) between about 1%and about 20% azelaic acid; and b) between about 0.1% and about 0.5%azithromycin, wherein the pharmaceutical formulation is administered tothe external surface of the upper eyelid daily for at least 1 month, andwherein administering the pharmaceutical formulation reduces a symptomof the dry eye disease.
 2. The method of claim 1, wherein the symptom ofdry eye disease is meibomian gland dysfunction, redness, stinging,burning, itching, light sensitivity, watery eyes, blurry vision,irregularities of the ocular surface, or damage to corneal orconjunctival epithelium and tissues.
 3. The method of claim 1, whereinthe dry eye disease is aqueous tear-deficient dry eye (ADDE).
 4. Themethod of claim 1, wherein the dry eye disease is evaporative dry eye(EDE).
 5. The method of claim 1, wherein ADDE and EDE are treatedsimultaneously.
 6. The method of claim 1, wherein the administration ofsaid pharmaceutical formulation further reduces a symptom ofblepharitis.
 7. The method of claim 6, wherein the blepharitis isanterior blepharitis.
 8. The method of claim 6, wherein the blepharitisis posterior blepharitis.
 9. The method of claim 6, wherein theblepharitis is both anterior blepharitis and posterior blepharitis. 10.The method of claim 1, wherein the administration of said pharmaceuticalformulation further improves the amount or quality of meibum produced.11. The method of claim 1, wherein the dry eye disease does not resultfrom bacterial infection, parasitic infection, or inflammation oftissue.
 12. The method of claim 1, wherein the concentration of azelaicacid is between about 5% and 20%.
 13. The method of claim 1, wherein theconcentration of azelaic acid is between about 5% and 15%.
 14. Themethod of claim 1, wherein the concentration of azelaic acid is betweenabout 5% and 15% and the concentration of azithromycin is between about0.4% and about 0.5%.
 15. The method of claim 1, wherein theconcentration of azelaic acid is about 10% and the concentration ofazithromycin is about 0.4%.
 16. The method of claim 1, wherein thepharmaceutical formulation is administered twice daily.
 17. The methodof claim 1, wherein the pharmaceutical formulation is administered dailyfor at least 6 months.
 18. The method of claim 1, wherein thepharmaceutical formulation is administered daily for at least 1 year.19. The method of claim 1, wherein the pharmaceutical formulation isadministered as a cream, gel, suspension, solution, ointment, or spray.20. The method of claim 19, wherein the pharmaceutical formulation isadministered as a cream.
 21. The method of claim 19, wherein thepharmaceutical formulation is administered as a gel.
 22. The method ofclaim 1, wherein the pharmaceutical formulation further comprises atleast one skin penetration enhancer.
 23. The method of claim 1, whereinthe pharmaceutical formulation further comprises at least one polyol.24. The method of claim 23, wherein the at least one polyol is propyleneglycol, polyethylene glycol, glycerol, erythritol, mannitol, orsorbitol.
 25. The method of claim 24, wherein the at least one polyol ispropylene glycol.
 26. The method of claim 1, wherein the concentrationof azelaic acid is between about 10% and 15%.
 27. The method of claim 1,wherein the pharmaceutical formulation is applied to the externalsurface of the upper eyelid and to an external surface of a lowereyelid.
 28. A method for treating dry eye disease comprising:administering to an external surface of an eyelid above upper lashes apharmaceutical formulation comprising: a) between about 1% and about 20%azelaic acid; and b) between about 0.1% and about 0.5% azithromycin,wherein the pharmaceutical formulation is administered to the externalsurface of the upper eyelid daily for at least 1 month, and whereinadministering the pharmaceutical formulation reduces a symptom of thedry eye disease.
 29. The method of claim 28, wherein the pharmaceuticalformulation comprises between about 5% and about 20% azelaic acid. 30.The method of claim 28, wherein the pharmaceutical formulation isapplied to the external surface of the upper eyelid above the upperlashes and to an external surface of a lower eyelid below the lowerlashes.